Inhibitors of human immunodeficiency virus replication

ABSTRACT

Compounds of formula I: wherein c, R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are defined herein, are useful as inhibitors of HIV replication.

RELATED APPLICATIONS

This application claims benefit of U.S. Ser. No. 60/988,327, filed Nov.15, 2007, which is herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions and methods forthe treatment of human immunodeficiency virus (HIV) infection. Inparticular, the present invention provides novel inhibitors of HIVreplication, pharmaceutical compositions containing such compounds andmethods for using these compounds in the treatment of HIV infection.More specifically, the present invention provides novel inhibitors ofthe HIV integrase enzyme, pharmaceutical compositions containing suchcompounds and methods for using these compounds to reduce HIVreplication and in the treatment of HIV infection.

BACKGROUND OF THE INVENTION

Acquired immune deficiency syndrome (AIDS) is caused by the humanimmunodeficiency virus (HIV), particularly the HIV-1 strain. Mostcurrently approved therapies for HIV infection target the viral reversetranscriptase and protease enzymes. There is additionally one approveddrug targeting gp41 to inhibit viral entry and one approved drugtargeting the integrase enzyme. Within the reverse transcriptaseinhibitor and protease inhibitor classes, resistance of HIV to existingdrugs is a problem. Therefore, it is important to discover and developnew antiretroviral compounds.

SUMMARY OF THE INVENTION

The present invention provides a novel series of compounds havinginhibitory activity against HIV replication. Furthermore, representativecompounds of the invention have activity as inhibitors in a cell-basedHIV replication assay. Further objects of this invention arise for theone skilled in the art from the following description and the examples.The compounds of the present invention have an affinity for the HIVintegrase enzyme. Therefore, the compounds of the invention may be usedto inhibit the activity of HIV integrase and may be used to reduce HIVreplication.

One aspect of the invention provides an isomer, racemate, enantiomer ordiastereomer of a compound of formula (I):

wherein

-   R² is selected from:    -   a) (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)haloalkyl,        (C₃₋₇)cycloalkyl, aryl, Het, halo, nitro or cyano;    -   b) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —S—R¹¹, —SO—R¹¹, —SO₂—R¹¹,        —(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,        —(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,        —(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or        —(C₁₋₆)alkylene-SO₂—R¹¹;        -   wherein R¹¹ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and        -   wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,            —O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl,            —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —C(═O)—NH₂,            —C(═O)—NH(C₁₋₄)alkyl, —C(═O)—N((C₁₋₄)alkyl)₂, —C(═O)-aryl,            —C(═O)—Het, NH₂, —NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂;        -   ii) (C₁₋₆)alkyl optionally substituted with —OH,            —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and        -   iii) aryl or Het, wherein each of the aryl and Het is            optionally substituted with halo, (C₁₋₆)alkyl or COOH; and    -   c) —O—R^(8a)        -   wherein R^(8a) is selected from H, (C₂₋₆)alkenyl,            (C₂₋₆)alkynyl,        -   (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het;    -   d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or        —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰ wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R¹⁰ is in each instance independently selected from R¹¹,            —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and            —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above; or-   R² may also be H, (C₁₋₆)alkyl or —O—(C₁₋₆)alkyl when one of R⁵ or R⁸    is other than H or when one of R⁶ or R⁷ is other than H, halo,    (C₁₋₆)alkyl or (C₁₋₆)haloalkyl,-   R⁵ and R⁸ are each independently selected from:    -   a) halo, nitro or cyano;    -   b) R¹¹, —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —SO—R¹¹,        —SO₂—R¹¹, —(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,        —(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,        —(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or        —(C₁₋₆)alkylene-SO₂—R¹¹;        -   wherein R¹¹ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and        -   wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,            —O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl, —SH, —SO(C₁₋₆)alkyl,            —SO₂(C₁₋₆)alkyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄)alkyl,            —C(═O)—N((C₁₋₄)alkyl)₂, —C(═O)-aryl, —C(═O)—Het, NH₂,            —NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂;        -   ii) (C₁₋₆)alkyl optionally substituted with —OH,            —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and        -   iii) aryl or Het, wherein each of the aryl and Het is            optionally substituted with halo, (C₁₋₆)alkyl or COOH; and    -   c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or        —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰ wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R¹⁰ is in each instance independently selected from R¹¹,            —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and            —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above;-   R⁶ is selected from:    -   a) (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl, nitro, cyano,        aryl and Het;    -   b) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —SO—R¹¹, —SO₂—R¹¹,        —(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,        —(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,        —(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or        —(C₁₋₆)alkylene-SO₂—R¹¹;        -   wherein R¹¹ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and    -   c) —N(R⁹)R¹⁰—O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or        —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰ wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R¹⁰ is in each instance independently selected from R¹¹,            —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and            —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above;            wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:    -   i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,        (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,        —O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl,        —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and        —N((C₁₋₆)alkyl)₂;    -   ii) (C₁₋₆)alkyl optionally substituted with —OH,        —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and    -   iii) aryl or Het, wherein each of the aryl and Het is optionally        substituted with halo, (C₁₋₆)alkyl or COOH; and-   R⁶ may also be H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl when at    least one of R⁵ or R⁸ is other than H or when R⁷ is other than H,    halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when R² is other than H,    (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl;-   R⁷ is selected from:    -   a) (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl, nitro, cyano,        aryl and Het;    -   b) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —S—R¹¹, —SO—R¹¹, —SO₂—R¹¹,        —(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,        —(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,        —(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or        —(C₁₋₆)alkylene-SO₂—R¹¹;        -   wherein R¹¹ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and    -   c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or        —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰ wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R¹⁰ is in each instance independently selected from R¹¹,            —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and            —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above;            wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:    -   i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,        (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,        —O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl,        —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and        —N((C₁₋₆)alkyl)₂;    -   ii) (C₁₋₆)alkyl optionally substituted with —OH,        —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and    -   iii) aryl or Het, wherein each of the aryl and Het is optionally        substituted with halo, (C₁₋₆)alkyl or COOH; and-   R⁷ may also be H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl when at    least one of R⁵ or R⁸ is other than H or when R⁶ is other than H,    halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when R² is other than H,    (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl;    -   or R⁵ and R⁶, together with the C to which they are attached, R⁶        and R⁷, together with the C to which they are attached, or R⁷        and R⁸, together with the C to which they are attached; may be        linked to form a 5- or 6-membered carbocycle or a 4- to        7-membered heterocycle optionally further containing 1 to 3        heteroatoms each independently selected from N, O and S, wherein        each S heteroatom may, independently and where possible, exist        in an oxidized state such that it is further bonded to one or        two oxygen atoms to form the groups SO or SO₂;    -   wherein the carbocycle or heterocycle is optionally substituted        with 1 to 3 substituents each independently selected from halo,        (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl,        —OH, —O(C₁₋₆)alkyl, —SH, —S(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and        —N((C₁₋₆)alkyl)₂;-   R³ is (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,    (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, aryl-(C₁₋₆)alkyl-, Het-(C₁₋₆)alkyl-    or —Y—R³¹, and bond c is a single bond; or-   R³ is (C₁₋₆)alkylidene and bond c is a double bond;    -   wherein Y is O or S and R³¹ is (C₁₋₆)alkyl, (C₁₋₆)haloalkyl,        (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl, aryl,        (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, aryl-(C₁₋₆)alkyl- or        Het-(C₁₋₆)alkyl-;    -   wherein each of the (C₁₋₆)alkylidene, (C₁₋₆)alkyl,        (C₁₋₆)haloalkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,        (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, Het-(C₁₋₆)alkyl- and —Y—R³¹ is        optionally substituted with 1 to 3 substituents each        independently selected from (C₁₋₆)alkyl, halo, cyano, oxo and        —O(C₁₋₆)alkyl;-   R⁴ is aryl or Het, wherein each of the aryl and Het is optionally    substituted with 1 to 5 substituents each independently selected    from halo, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,    (C₃₋₇)cycloalkyl, —OH, —O(C₁₋₆)alkyl, —SH, —S(C₁₋₆)alkyl, —NH₂,    —NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂; wherein the (C₁₋₆)alkyl is    optionally substituted with hydroxy, —O(C₁₋₆)alkyl, cyano or oxo;-   wherein Het is a 4- to 7-membered saturated, unsaturated or aromatic    heterocycle having 1 to 4 heteroatoms each independently selected    from O, N and S, or a 7- to 14-membered saturated, unsaturated or    aromatic heteropolycycle having wherever possible 1 to 5    heteroatoms, each independently selected from O, N and S; wherein    each N heteroatom may, independently and where possible, exist in an    oxidized state such that it is further bonded to an oxygen atom to    form an N-oxide group and wherein each S heteroatom may,    independently and where possible, exist in an oxidized state such    that it is further bonded to one or two oxygen atoms to form the    groups SO or SO₂;-   or a salt or an ester thereof.

Another aspect of this invention provides a compound of formula (I) or apharmaceutically acceptable salt or ester thereof, as a medicament.

Still another aspect of this invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt or ester thereof;and one or more pharmaceutically acceptable carriers.

According to an embodiment of this aspect, the pharmaceuticalcomposition according to this invention additionally comprises at leastone other antiviral agent.

The invention also provides the use of a pharmaceutical composition asdescribed hereinabove for the treatment of an HIV infection in a mammalhaving or at risk of having the infection.

A further aspect of the invention involves a method of treating an HIVinfection in a mammal having or at risk of having the infection, themethod comprising administering to the mammal a therapeuticallyeffective amount of a compound of formula (I), a pharmaceuticallyacceptable salt or ester thereof, or a composition thereof as describedhereinabove.

Another aspect of the invention involves a method of treating an HIVinfection in a mammal having or at risk of having the infection, themethod comprising administering to the mammal a therapeuticallyeffective amount of a combination of a compound of formula (I) or apharmaceutically acceptable salt or ester thereof, and at least oneother antiviral agent; or a composition thereof.

Also within the scope of this invention is the use of a compound offormula (I) as described herein, or a pharmaceutically acceptable saltor ester thereof, for the treatment of an HIV infection in a mammalhaving or at risk of having the infection.

Another aspect of this invention provides the use of a compound offormula (I) as described herein, or a pharmaceutically acceptable saltor ester thereof, for the manufacture of a medicament for the treatmentof an HIV infection in a mammal having or at risk of having theinfection.

An additional aspect of this invention refers to an article ofmanufacture comprising a composition effective to treat an HIVinfection; and packaging material comprising a label which indicatesthat the composition can be used to treat infection by HIV; wherein thecomposition comprises a compound of formula (I) according to thisinvention or a pharmaceutically acceptable salt or ester thereof.

Still another aspect of this invention relates to a method of inhibitingthe replication of HIV comprising exposing the virus to an effectiveamount of the compound of formula (I), or a salt or ester thereof, underconditions where replication of HIV is inhibited.

Further included in the scope of the invention is the use of a compoundsof formula (I) to inhibit the activity of the HIV integrase enzyme.

Further included in the scope of the invention is the use of a compoundof formula (I), or a salt or ester thereof, to inhibit the replicationof HIV.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the following definitions apply unless otherwise noted:

The term “substituent”, as used herein and unless specified otherwise,is intended to mean an atom, radical or group which may be bonded to acarbon atom, a heteroatom or any other atom which may form part of amolecule or fragment thereof, which would otherwise be bonded to atleast one hydrogen atom. Substituents contemplated in the context of aspecific molecule or fragment thereof are those which give rise tochemically stable compounds, such as are recognized by those skilled inthe art.

The term “(C_(1-n))alkyl” as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanacyclic, straight or branched chain alkyl radicals containing from 1 ton carbon atoms. “(C₁₋₆)alkyl” includes, but is not limited to, methyl,ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (iso-propyl),1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tent-butyl), pentyl and hexyl. The abbreviation Medenotes a methyl group; Et denotes an ethyl group, Pr denotes a propylgroup, iPr denotes a 1-methylethyl group, Bu denotes a butyl group andtBu denotes a 1,1-dimethylethyl group.

The term “(C_(1-n))alkylidene” as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanacyclic, straight or branched chain alkyl radicals containing from 1 ton carbon atoms which are bonded to a molecule or fragment thereof, as asubstituent thereof, by a double bond. “(C₁₋₆)alkylidene” includes, butis not limited to, CH₂═, CH₃CH═, CH₃CH₂CH═,

groups. Unless specified otherwise, the term “(C_(2-n))alkylidene” isunderstood to encompass individual stereoisomers where possible,including but not limited to (E) and (Z) isomers, and mixtures thereof.When a (C_(2-n))alkylidene group is substituted, it is understood to besubstituted on any carbon atom thereof which would otherwise bear ahydrogen atom, unless specified otherwise, such that the substitutionwould give rise to a chemically stable compound, such as are recognizedby those skilled in the art.

The term “(C_(1-n))alkylene” as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanacyclic, straight or branched chain divalent alkyl radicals containingfrom 1 to n carbon atoms. “(C₁₋₆)alkylene” includes, but is not limitedto, —CH₂—, —CH₂CH₂—,

The term “(C_(2-n))alkenyl”, as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanan unsaturated, acyclic straight or branched chain radical containingtwo to n carbon atoms, at least two of which are bonded to each other bya double bond. Examples of such radicals include, but are not limitedto, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl. Unlessspecified otherwise, the term “(C_(2-n))alkenyl” is understood toencompass individual stereoisomers where possible, including but notlimited to (E) and (Z) isomers, and mixtures thereof. When a(C_(2-n))alkenyl group is substituted, it is understood to besubstituted on any carbon atom thereof which would otherwise bear ahydrogen atom, unless specified otherwise, such that the substitutionwould give rise to a chemically stable compound, such as are recognizedby those skilled in the art.

The term “(C_(2-n))alkynyl”, as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanan unsaturated, acyclic straight or branched chain radical containingtwo to n carbon atoms, at least two of which are bonded to each other bya triple bond. Examples of such radicals include, but are not limitedto, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. When a(C_(2-n))alkynyl group is substituted, it is understood to besubstituted on any carbon atom thereof which would otherwise bear ahydrogen atom, unless specified otherwise, such that the substitutionwould give rise to a chemically stable compound, such as are recognizedby those skilled in the art.

The term “(C_(3-m))cycloalkyl” as used herein, wherein m is an integer,either alone or in combination with another radical, is intended to meana cycloalkyl substituent containing from 3 to m carbon atoms andincludes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

The term “(C_(3-m))cycloalkyl-(C_(1-n))alkyl-” as used herein, wherein nand m are both integers, either alone or in combination with anotherradical, is intended to mean an alkyl radical having 1 to n carbon atomsas defined above which is itself substituted with a cycloalkyl radicalcontaining from 3 to m carbon atoms as defined above. Examples of(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl- include, but are not limited to,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclobutylethyl, 2-cyclobutylethyl, 1-cyclopentylethyl,2-cyclopentylethyl, 1-cyclohexylethyl and 2-cyclohexylethyl. When a(C_(3-m))cycloalkyl-(C_(1-n))alkyl-group is substituted, it isunderstood that substituents may be attached to either the cycloalkyl orthe alkyl portion thereof or both, unless specified otherwise, such thatthe substitution would give rise to a chemically stable compound, suchas are recognized by those skilled in the art.

The term “aryl” as used herein, either alone or in combination withanother radical, is intended to mean a carbocyclic aromatic monocyclicgroup containing 6 carbon atoms which may be further fused to a second5- or 6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl and dihydronaphthyl.

The term “aryl-(C_(1-n))alkyl-” as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanan alkyl radical having 1 to n carbon atoms as defined above which isitself substituted with an aryl radical as defined above. Examples ofaryl-(C_(1-n))alkyl- include, but are not limited to, phenylmethyl(benzyl), 1-phenylethyl, 2-phenylethyl and phenylpropyl. When anaryl-(C_(1-n))alkyl-group is substituted, it is understood thatsubstituents may be attached to either the aryl or the alkyl portionthereof or both, unless specified otherwise, such that the substitutionwould give rise to a chemically stable compound, such as are recognizedby those skilled in the art.

The term “carbocycle” as used herein, either alone or in combinationwith another radical, is intended to mean a cyclic compound, eitheraromatic or non-aromatic, saturated or unsaturated, in which all of thering members are carbon atoms. The carbocycle group may containing 5 or6 carbon atom and may be further fused to a second 5- or 6-memberedcarbocyclic group which may be aromatic, saturated or unsaturated.

The term “Het” as used herein, either alone or in combination withanother radical, is intended to mean a 4- to 7-membered saturated,unsaturated or aromatic heterocycle having 1 to 4 heteroatoms eachindependently selected from O, N and S, or a 7- to 14-memberedsaturated, unsaturated or aromatic heteropolycycle having whereverpossible 1 to 5 heteroatoms, each independently selected from O, N andS, unless specified otherwise; wherein each N heteroatom may,independently and where possible, exist in an oxidized state such thatit is further bonded to an oxygen atom to form an N-oxide group andwherein each S heteroatom may, independently and where possible, existin an oxidized state such that it is further bonded to one or two oxygenatoms to form the groups SO or SO₂. When a Het group is substituted, itis understood that substituents may be attached to any carbon atom orheteroatom thereof which would otherwise bear a hydrogen atom, unlessspecified otherwise, such that the substitution would give rise to achemically stable compound, such as are recognized by those skilled inthe art.

The term “Het-(C_(1-n))alkyl-” as used herein and unless specifiedotherwise, wherein n is an integer, either alone or in combination withanother radical, is intended to mean an alkyl radical having 1 to ncarbon atoms as defined above which is itself substituted with a Hetsubstituent as defined above. Examples of Het-(C_(1-n))alkyl- include,but are not limited to, thienylmethyl, furylmethyl, piperidinylethyl,2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl,quinolinylpropyl, and the like. When an Het-(C_(1-n))alkyl-group issubstituted, it is understood that substituents may be attached toeither the Het or the alkyl portion thereof or both, unless specifiedotherwise, such that the substitution would give rise to a chemicallystable compound, such as are recognized by those skilled in the art.

The term “heteroatom” as used herein is intended to mean O, S or N.

The term “heterocycle” as used herein and unless specified otherwise,either alone or in combination with another radical, is intended to meana 3- to 7-membered saturated, unsaturated or aromatic heterocyclecontaining from 1 to 4 heteroatoms each independently selected from O, Nand S; or a monovalent radical derived by removal of a hydrogen atomtherefrom. Examples of such heterocycles include, but are not limitedto, azetidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,thiazolidine, oxazolidine, pyrrole, thiophene, furan, pyrazole,imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole,tetrazole, piperidine, piperazine, azepine, diazepine, pyran,1,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide,pyridazine, pyrazine and pyrimidine, and saturated, unsaturated andaromatic derivatives thereof.

The term “heteropolycycle” as used herein and unless specifiedotherwise, either alone or in combination with another radical, isintended to mean a heterocycle as defined above fused to one or moreother cycle, including a carbocycle, a heterocycle or any other cycle;or a monovalent radical derived by removal of a hydrogen atom therefrom.Examples of such heteropolycycles include, but are not limited to,indole, isoindole, benzimidazole, benzothiophene, benzofuran,benzopyran, benzodioxole, benzodioxane, benzothiazole, quinoline,isoquinoline, and naphthyridine, and saturated, unsaturated and aromaticderivatives thereof.

The term “halo” as used herein is intended to mean a halogen substituentselected from fluoro, chloro, bromo or iodo.

The term “(C_(1-n))haloalkyl” as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanan alkyl radical having 1 to n carbon atoms as defined above wherein oneor more hydrogen atoms are each replaced by a halo substituent. Examplesof (C_(1-n))haloalkyl include but are not limited to chloromethyl,chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl anddifluoroethyl.

The terms “—O—(C_(1-n))alkyl” or “(C_(1-n))alkoxy” as used hereininterchangeably, wherein n is an integer, either alone or in combinationwith another radical, is intended to mean an oxygen atom further bondedto an alkyl radical having 1 to n carbon atoms as defined above.Examples of —O—(C_(1-n))alkyl include but are not limited to methoxy(CH₃O—), ethoxy (CH₃CH₂O—), propoxy (CH₃CH₂CH₂O—), 1-methylethoxy(iso-propoxy; (CH₃)₂CH—O—) and 1,1-dimethylethoxy (tert-butoxy;(CH₃)₃C—O—). When an —O—(C_(1-n))alkyl radical is substituted, it isunderstood to be substituted on the (C_(1-n))alkyl portion thereof, suchthat the substitution would give rise to a chemically stable compound,such as are recognized by those skilled in the art.

The term “—O—(C_(1-n))haloalkyl”, wherein n is an integer, either aloneor in combination with another radical, is intended to mean an oxygenatom further bonded to a haloalkyl radical having 1 to n carbon atoms asdefined above. When an —O—(C_(1-n))haloalkyl radical is substituted, itis understood to be substituted on the (C_(1-n))alkyl portion thereof.

The terms “—S—(C_(1-n))alkyl” or “(C_(1-n))alkylthio” as used hereininterchangeably, wherein n is an integer, either alone or in combinationwith another radical, is intended to mean an sulfur atom further bondedto an alkyl radical having 1 to n carbon atoms as defined above.Examples of —S—(C_(1-n))alkyl include but are not limited to methylthio(CH₃S—), ethylthio (CH₃CH₂S—), propylthio (CH₃CH₂CH₂S—),1-methylethylthio (isopropylthio; (CH₃)₂CH—S—) and 1,1-dimethylethylthio(tert-butylthio; (CH₃)₃C—S—). When —S—(C_(1-n))alkyl radical, or anoxidized derivative thereof, such as an —SO—(C_(1-n))alkyl radical or an—SO₂—(C_(1-n))alkyl radical, is substituted, each is understood to besubstituted on the (C_(1-n))alkyl portion thereof, such that thesubstitution would give rise to a chemically stable compound, such asare recognized by those skilled in the art.

The term “oxo” as used herein is intended to mean an oxygen atomattached to a carbon atom as a substituent by a double bond (═O).

The term “thioxo” as used herein is intended to mean a sulfur atomattached to a carbon atom as a substituent by a double bond (═S).

The term “cyano” as used herein is intended to mean a carbon atomattached to a nitrogen atom as a substituent by a triple bond.

The term “COOH” as used herein is intended to mean a carboxyl group(—C(═O)—OH). It is well known to one skilled in the art that carboxylgroups may be substituted by functional group equivalents. Examples ofsuch functional group equivalents contemplated in this inventioninclude, but are not limited to, esters, amides, imides, boronic acids,phosphonic acids, phosphoric acids, tetrazoles, triazoles,N-acylsulfamides (RCONHSO₂NR₂), and N-acylsulfonamides (RCONHSO₂R).

The term “functional group equivalent” as used herein is intended tomean an atom or group that may replace another atom or group which hassimilar electronic, hybridization or bonding properties.

The term “protecting group” as used herein is intended to meanprotecting groups that can be used during synthetic transformation,including but not limited to examples which are listed in Greene,“Protective Groups in Organic Chemistry”, John Wiley & Sons, New York(1981), and more recent editions thereof, herein incorporated byreference.

The following designation

is used in sub-formulas to indicate the bond which is connected to therest of the molecule as defined.

The term “salt thereof” as used herein is intended to mean any acidand/or base addition salt of a compound according to the invention,including but not limited to a pharmaceutically acceptable salt thereof.

The term “pharmaceutically acceptable salt” as used herein is intendedto mean a salt of a compound according to the invention which is, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, generally water or oil-soluble ordispersible, and effective for their intended use. The term includespharmaceutically-acceptable acid addition salts andpharmaceutically-acceptable base addition salts. Lists of suitable saltsare found in, for example, S. M. Birge et al., J. Pharm. Sci., 1977, 66,pp. 1-19, herein incorporated by reference.

The term “pharmaceutically-acceptable acid addition salt” as used hereinis intended to mean those salts which retain the biologicaleffectiveness and properties of the free bases and which are notbiologically or otherwise undesirable, formed with inorganic acidsincluding but not limited to hydrochloric acid, hydrobromic acid,sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like,and organic acids including but not limited to acetic acid,trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid,benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid,camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid,ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoricacid, hemisulfic acid, hexanoic acid, formic acid, fumaric acid,2-hydroxyethanesulfonic acid (isethionic acid), lactic acid,hydroxymaleic acid, malic acid, malonic acid, mandelic acid,mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid,nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid,pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid,propionic acid, pyruvic acid, salicylic acid, stearic acid, succinicacid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoicacid and the like.

The term “pharmaceutically-acceptable base addition salt” as used hereinis intended to mean those salts which retain the biologicaleffectiveness and properties of the free acids and which are notbiologically or otherwise undesirable, formed with inorganic basesincluding but not limited to ammonia or the hydroxide, carbonate, orbicarbonate of ammonium or a metal cation such as sodium, potassium,lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum andthe like. Particularly preferred are the ammonium, potassium, sodium,calcium, and magnesium salts. Salts derived frompharmaceutically-acceptable organic nontoxic bases include but are notlimited to salts of primary, secondary, and tertiary amines, quaternaryamine compounds, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion-exchange resins, such asmethylamine, dimethylamine, trimethylamine, ethylamine, diethylamine,triethylamine, isopropylamine, tripropylamine, tributylamine,ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, tetramethylammonium compounds, tetraethylammoniumcompounds, pyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylmorpholine, dicyclohexylamine, dibenzylamine,N,N-dibenzylphenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamine,polyamine resins and the like. Particularly preferred organic nontoxicbases are isopropylamine, diethylamine, ethanolamine, trimethylamine,dicyclohexylamine, choline, and caffeine.

The term “ester thereof” as used herein is intended to mean any ester ofa compound according to the invention in which any of the —COOHsubstituents of the molecule is replaced by a —COOR substituent, inwhich the R moiety of the ester is any carbon-containing group whichforms a stable ester moiety, including but not limited to alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, each of which being optionally furthersubstituted. The term “ester thereof” includes but is not limited topharmaceutically acceptable esters thereof.

The term “pharmaceutically acceptable ester” as used herein is intendedto mean esters of the compound according to the invention in which anyof the COOH substituents of the molecule are replaced by a —COORsubstituent, in which the R moiety of the ester is selected from alkyl(including, but not limited to, methyl, ethyl, propyl, 1-methylethyl,1,1-dimethylethyl, butyl); alkoxyalkyl (including, but not limited tomethoxymethyl); acyloxyalkyl (including, but not limited toacetoxymethyl); arylalkyl (including, but not limited to, benzyl);aryloxyalkyl (including, but not limited to, phenoxymethyl); and aryl(including, but not limited to phenyl) optionally substituted withhalogen, (C₁₋₄)alkyl or (C₁₋₄)alkoxy. Other suitable esters can be foundin Design of Prodrugs, Bundgaard, H. Ed. Elsevier (1985), hereinincorporated by reference. Such pharmaceutically acceptable esters areusually hydrolyzed in vivo when injected into a mammal and transformedinto the acid form of the compound according to the invention. Withregard to the esters described above, unless otherwise specified, anyalkyl moiety present preferably contains 1 to 16 carbon atoms, morepreferably 1 to 6 carbon atoms. Any aryl moiety present in such esterspreferably comprises a phenyl group. In particular the esters may be a(C₁₋₁₆)alkyl ester, an unsubstituted benzyl ester or a benzyl estersubstituted with at least one halogen, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, nitroor trifluoromethyl.

The term “mammal” as used herein is intended to encompass humans, aswell as non-human mammals which are susceptible to infection by HIV.Non-human mammals include but are not limited to domestic animals, suchas cows, pigs, horses, dogs, cats, rabbits, rats and mice, andnon-domestic animals.

The term “treatment” as used herein is intended to mean theadministration of a compound or composition according to the presentinvention to alleviate or eliminate symptoms of HIV infection and/or toreduce viral load in a patient. The term “treatment” also encompassesthe administration of a compound or composition according to the presentinvention post-exposure of the individual to the virus but before theappearance of symptoms of the disease, and/or prior to the detection ofthe virus in the blood, to prevent the appearance of symptoms of thedisease and/or to prevent the virus from reaching detectable levels inthe blood, and the administration of a compound or composition accordingto the present invention to prevent perinatal transmission of HIV frommother to baby, by administration to the mother before giving birth andto the child within the first days of life.

The term “antiviral agent” as used herein is intended to mean an agentthat is effective to inhibit the formation and/or replication of a virusin a mammal, including but not limited to agents that interfere witheither host or viral mechanisms necessary for the formation and/orreplication of a virus in a mammal.

The term “inhibitor of HIV replication” as used herein is intended tomean an agent capable of reducing or eliminating the ability of HIV toreplicate in a host cell, whether in vitro, ex vivo or in vivo.

The term “HIV integrase” or “integrase”, used herein interchangeably,means the integrase enzyme encoded by the human immunodeficiency virustype 1.

The term “therapeutically effective amount” means an amount of acompound according to the invention, which when administered to apatient in need thereof, is sufficient to effect treatment fordisease-states, conditions, or disorders for which the compounds haveutility. Such an amount would be sufficient to elicit the biological ormedical response of a tissue system, or patient that is sought by aresearcher or clinician. The amount of a compound according to theinvention which constitutes a therapeutically effective amount will varydepending on such factors as the compound and its biological activity,the composition used for administration, the time of administration, theroute of administration, the rate of excretion of the compound, theduration of the treatment, the type of disease-state or disorder beingtreated and its severity, drugs used in combination with orcoincidentally with the compounds of the invention, and the age, bodyweight, general health, sex and diet of the patient. Such atherapeutically effective amount can be determined routinely by one ofordinary skill in the art having regard to their own knowledge, thestate of the art, and this disclosure.

Preferred Embodiments

In the following preferred embodiments, groups and substituents of thecompounds of formula (I):

according to this invention are described in detail.Core:

-   Core-A: In one embodiment, the compounds of the invention are    represented by formula (Ia):

-   -   wherein c, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined herein.

It will be apparent to a person skilled in the art that, when bond c isa single bond, the carbon atom bonded to the —COOH and R³ substituentscan exist in two possible stereochemical configurations, as shown informulas (Ib) and (Ic) below:

wherein R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined herein.

It has been found that compounds of formula (Ib) have improved activityover compounds of formula (Ic).

-   Core-B: In one embodiment, the compounds of the invention are    represented by formula (Ib):

-   -   wherein R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined herein.

-   Core-C: In an alternative embodiment, the compounds of the invention    are represented by formula (Ic):

-   -   wherein R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined herein.

Any and each individual definition of the Core as set out herein may becombined with any and each individual definition of R², R³, R⁴, R⁵, R⁶,R⁷ and R⁸ as set out herein.

R²:

-   R²-A: In one embodiment, R² is selected from:    -   a) (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)haloalkyl,        (C₃₋₇)cycloalkyl, aryl, Het, halo, nitro or cyano;    -   b) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —S—R¹¹, —SO—R¹¹, —SO₂—R¹¹,        —(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,        —(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,        —(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or        —(C₁₋₆)alkylene-SO₂—R¹¹;        -   wherein R¹¹ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and        -   wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,            —O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl,            —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —C(═O)—NH₂,            —C(═O)—NH(C₁₋₄)alkyl, —C(═O)—N((C₁₋₄)alkyl)₂, —C(═O)-aryl,            —C(═O)—Het, NH₂, —NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂;        -   ii) (C₁₋₆)alkyl optionally substituted with —OH,            —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and        -   iii) aryl or Het, wherein each of the aryl and Het is            optionally substituted with halo, (C₁₋₆)alkyl or COOH; and    -   c) —O—R^(8a)        -   wherein R^(8a) is selected from H, (C₂₋₆)alkenyl,            (C₂₋₆)alkynyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and            Het;    -   d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or        —(C₁₋₆)alkylene-SO₂—N(R⁹)R^(w) wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R¹⁰ is in each instance independently selected from R¹¹,            —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and            —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above; or-   R² may also be H, (C₁₋₆)alkyl or —O—(C₁₋₆)alkyl when one of R⁵ or R⁸    is other than H or when one of R⁶ or R⁷ is other than H, halo,    (C₁₋₆)alkyl or (C₁₋₆)haloalkyl.-   R²-B: In an alternative embodiment, R² is (C₁₋₆)alkyl or    —O(C₁₋₆)alkyl when one of R⁵ or R⁸ is other than H or when one of R⁶    or R⁷ is other than H, halo, (C₁₋₆)alkyl or (C₁₋₆)haloalkyl.-   R²-C: In another embodiment, R² is (C₁₋₆)alkyl when one of R⁵ and R⁸    is other than H or when one of R⁶ or R⁷ is other than H, halo,    (C₁₋₆)alkyl or (C₁₋₆)haloalkyl.-   R²-D: In another embodiment, R² is —CH₃ or —CH₂CH₃ when one of R⁵ or    R⁸ is other than H or when one of R⁶ or R⁷ is other than H, halo,    (C₁₋₆)alkyl or (C₁₋₆)haloalkyl.-   R²-E: In another embodiment, R² is —CH₃ when one of R⁵ or R⁸ is    other than H or when one of R⁶ or R⁷ is other than H, halo,    (C₁₋₆)alkyl or (C₁₋₆)haloalkyl.-   R²-F: In another embodiment, R² is —(C₁₋₆)alkylene-Het,    —(C₁₋₆)alkylene-aryl, —(C₁₋₆)alkylene-O-Het, —(C₁₋₆)alkylene-O-aryl,    Het or aryl, all being optionally substituted with (C₁₋₆)alkyl,    (C₁₋₆)haloalkyl, or —O(C₁₋₆)alkyl.-   R²-G: In another embodiment, R² is —(C₁₋₆)alkylene-Het,    —(C₁₋₆)alkylene-aryl, —(C₁₋₆)alkylene-O-Het or    —(C₁₋₆)alkylene-O-aryl.-   R²-H: In another embodiment, R² is —(C₁₋₆)alkylene-Het,    —(C₁₋₆)alkylene-aryl, —(C₁₋₆)alkylene-O-Het or    —(C₁₋₆)alkylene-O-aryl; or    -   (C₁₋₆)alkyl, when one of R⁵ or R⁸ is other than H or when one of        R⁶ or R⁷ is other than H, halo, (C₁₋₆)alkyl or (C₁₋₆)haloalkyl.-   R²-I: In another embodiment, R² is

or

-   -   CH₃, when one of R⁵ or R⁸ is other than H or when one of R⁶ or        R⁷ is other than H, halo, (C₁₋₆)alkyl or (C₁₋₆)haloalkyl.

Any and each individual definition of R² as set out herein may becombined with any and each individual definition of the Core, c, R³, R⁴,R⁵, R⁶, R⁷ and R⁸ as set out herein.

R³:

-   R³-A: In one embodiment, R³ is (C₁₋₆)alkyl, (C₁₋₆)haloalkyl,    (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-,    aryl-(C₁₋₆)alkyl-, Het-(C₁₋₆)alkyl- or —Y—R³¹, and bond c is a    single bond; or    -   R³ is (C₁₋₆)alkylidene and bond c is a double bond;    -   wherein Y is O or S and R³¹ is (C₁₋₆)alkyl, (C₁₋₆)haloalkyl,        (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl, aryl,        (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, aryl-(C₁₋₆)alkyl- or        Het-(C₁₋₆)alkyl-;    -   wherein each of the (C₁₋₆)alkylidene, (C₁₋₆)alkyl,        (C₁₋₆)haloalkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,        (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, Het-(C₁₋₆)alkyl- and —Y—R³¹ is        optionally substituted with 1 to 3 substituents each        independently selected from (C₁₋₆)alkyl, halo, cyano, oxo and        —O(C₁₋₆)alkyl.-   R³-B: In one embodiment, R³ is (C₁₋₆)alkyl, (C₁₋₆)haloalkyl,    (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-,    aryl-(C₁₋₆)alkyl- or Het-(C₁₋₆)alkyl-;    -   wherein each of the (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, (C₂₋₆)alkenyl,        (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, aryl-(C₁₋₆)alkyl-        and Het-(C₁₋₆)alkyl- is optionally substituted with 1 to 3        substituents each independently selected from (C₁₋₆)alkyl, halo,        cyano, oxo and —O(C₁₋₆)alkyl; and    -   bond c is a single bond.-   R³-C: In another embodiment, R³ is (C₁₋₆)alkyl or (C₂₋₆)alkenyl; and    -   bond c is a single bond.-   R³-D: In an alternative embodiment, R³ is —Y—(C₁₋₆)alkyl,    —Y—(C₂₋₆)alkenyl, —Y—(C₂₋₆)alkynyl, —Y—(C₃₋₇)cycloalkyl, —Y-aryl,    (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-Y—, aryl-(C₁₋₆)alkyl-Y— or    Het-(C₁₋₆)alkyl-Y—;    -   wherein Y is O or S; and    -   wherein each of the —Y—(C₁₋₆)alkyl, —Y—(C₂₋₆)alkenyl,        —Y—(C₂₋₆)alkynyl, —Y—(C₃₋₇)cycloalkyl, —Y-aryl,        (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-Y—, and Het-(C₁₋₆)alkyl-Y— is        optionally substituted with 1 to 3 substituents each        independently selected from (C₁₋₆)alkyl, halo, cyano, oxo and        —O(C₁₋₆)alkyl;    -   and    -   bond c is a single bond.-   R³-E: In another embodiment, R³ is —O—(C₁₋₆)alkyl, —O—(C₂₋₆)alkenyl,    —O—(C₂₋₆)alkynyl, —O—(C₃₋₇)cycloalkyl, —O-aryl,    (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-O—, aryl-(C₁₋₆)alkyl-O— or    Het-(C₁₋₆)alkyl-O—;    -   wherein each of the —O—(C₁₋₆)alkyl, —O—(C₂₋₆)alkenyl,        —O—(C₂₋₆)alkynyl, —O—(C₃₋₇)cycloalkyl, —O-aryl,        (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-O—, aryl-(C₁₋₆)alkyl-O— and        Het-(C₁₋₆)alkyl-O— is optionally substituted with 1 to 3        substituents each independently selected from (C₁₋₆)alkyl, halo,        cyano, oxo and —O(C₁₋₆)alkyl;    -   and    -   bond c is a single bond.-   R³-F: In another embodiment, R³ is —O(C₁₋₆)alkyl,    —O—(C₁₋₆)haloalkyl, —O—(C₂₋₆)alkenyl, —O(C₂₋₆)alkynyl,    —O—(C₃₋₇)cycloalkyl, —O-aryl, (C₃₋₇)cycloalkyl-(C₁₋₃)alkyl-O— or    Het-(C₁₋₃)alkyl-O—;    -   wherein Het is a 5- or 6-membered heterocycle having 1 to 3        heteroatoms each independently selected from N, O and S; and    -   wherein each of the —O(C₁₋₆)alkyl, —O—(C₃₋₇)cycloalkyl and        Het-(C₁₋₃)alkyl-O— is optionally substituted with 1 to 3        substituents each independently selected from (C₁₋₃)alkyl,        cyano, oxo and —O(C₁₋₆)alkyl; and    -   bond c is a single bond.-   R³-G: In another embodiment, R³ is —O(C₁₋₆)alkyl,    —O—(C₁₋₆)haloalkyl, —O(C₂₋₆)alkenyl, —O(C₂₋₆)alkynyl or    —O—(C₃₋₇)cycloalkyl;    -   wherein each of the —O(C₁₋₆)alkyl and —O—(C₃₋₇)cycloalkyl is        optionally substituted with 1 to 3 substituents each        independently selected from (C₁₋₃)alkyl, cyano, oxo and        —O(C₁₋₆)alkyl; and    -   bond c is a single bond.-   R³—H: In another embodiment, R³ is —O(C₁₋₄)alkyl; wherein the    —O(C₁₋₄)alkyl is optionally substituted with 1 to 2 substituents    each independently selected from cyano, oxo and —O(C₁₋₆)alkyl; and    -   bond c is a single bond.-   R³-I: In another embodiment, R³ is —OC(CH₃)₃; and bond c is a single    bond.-   R³-J: In another embodiment, R³ is selected from:

Any and each individual definition of c and R³ as set out herein may becombined with any and each individual definition of the Core, R², R⁴,R⁵, R⁶, R⁷ and R⁸ as set out herein.

R⁴:

-   R⁴-A: In one embodiment, R⁴ is aryl optionally substituted with 1 to    5 substituents each independently selected from halo, (C₁₋₆)alkyl,    (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, —OH,    —O(C₁₋₆)alkyl, —SH, —S(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and    —N((C₁₋₆)alkyl)₂; wherein the (C₁₋₆)alkyl is optionally substituted    with hydroxy, —O(C₁₋₆)alkyl, cyano or oxo.-   R⁴-B: In another embodiment, R⁴ is naphthyl or phenyl, wherein the    phenyl is optionally substituted with 1 to 3 substituents each    independently selected from halo, (C₁₋₄)alkyl, (C₂₋₄)alkenyl,    (C₁₋₄)haloalkyl, (C₃₋₇)cycloalkyl, —OH, —SH, —S(C₁₋₄)alkyl, —NH₂,    —NH(C₁₋₄)alkyl and —N((C₁₋₄)alkyl)₂;    -   wherein the (C₁₋₄)alkyl is optionally substituted with hydroxy,        —O(C₁₋₆)alkyl, cyano or oxo.-   R⁴-C: In another embodiment, R⁴ is phenyl optionally substituted    with 1 to 3 substituents each independently selected from halo,    (C₁₋₄)alkyl and (C₁₋₄)haloalkyl.-   R⁴-D: In another embodiment, R⁴ is phenyl optionally substituted    with 1 or 2 substituents each independently selected from F, Cl, Br,    —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂ and —C(CH₃)₃.-   R⁴-E: In another embodiment, R⁴ is a group of formula:

-   -   wherein R⁴¹ is selected from halo, (C₁₋₄)alkyl and        (C₁₋₄)haloalkyl.

-   R⁴-F: In an alternative embodiment, R⁴ is Het optionally substituted    with 1 to 4 substituents each independently selected from halo,    (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, —OH,    —O(C₁₋₆)alkyl, —SH, —S(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and    —N((C₁₋₆)alkyl)₂; wherein the (C₁₋₆)alkyl is optionally substituted    with hydroxy, cyano or oxo.

-   R⁴-G: In another alternative embodiment, R⁴ is Het optionally    substituted with 1 to 3 substituents each independently selected    from halo and (C₁₋₆)alkyl;    -   wherein the Het is a 5- or 6-membered heterocycle having 1 to 3        heteroatoms each independently selected from N, O and S; or the        Het is a 9- or 10-membered heteropolycycle having 1 to 3        heteroatoms each independently selected from N, O and S.

-   R⁴-H: In another alternative embodiment, R⁴ is Het optionally    substituted with 1 to 3 substituents each independently selected    from halo, (C₁₋₆)alkyl and —O(C₁₋₆)alkyl;    -   wherein the Het is selected from:

-   R⁴-I: In another alternative embodiment, R⁴ is Het optionally    substituted with 1 to 3 substituents each independently selected    from halo, (C₁₋₆)alkyl and —O(C₁₋₆)alkyl;    -   wherein the Het is selected from:

-   R⁴-J: In another alternative embodiment, R⁴ is selected from:

-   R⁴-K: In another alternative embodiment, R⁴ is selected from:

One skilled in the art will recognize that when the R⁴ substituent isnot symmetrically substituted about the axis of rotation of the bondattaching R⁴ to Core, rotational isomers or atropisomers are possible.Compounds of the invention in which the R⁴ substituent is notsymmetrically substituted about the axis of rotation of the bondattaching R⁴ to Core and in which the carbon atom bonded to the —COOHand R³ substituents is chiral, as described above, will have two chiralcenters, a chiral carbon atom and a rotational axis of asymmetry, andthus the atropisomers will exist as diastereomers. However, individualdiastereomeric atropisomers may or may not be detectable and/orseparable, depending upon the relative amounts of each atropisomerformed during synthesis, present at equilibrium, and the degree ofsteric hindrance to rotation about the C-4 chiral axis, and therefore,the rate at which interconversion between these atropoisomers occurs.Once separated, individual atropoisomers may be very stable orinterconvert, rapidly or slowly, with each other to form an equilibriummixture of atropoisomers.

-   R⁴-L: In another alternative embodiment, R⁴ is selected from:

Any and each individual definition of R⁴ as set out herein may becombined with any and each individual definition of the Core, c, R², R³,R⁵, R⁶, R⁷ and R⁸ as set out herein.

R⁵:

-   R⁵-A: In one embodiment, R⁵ is selected from:    -   a) halo, nitro or cyano;    -   b) R¹¹, —C(═O)—R¹¹, —C(═O)—O—R¹¹, —S—R¹¹, —SO—R¹¹, —SO₂—R¹¹,        —(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,        —(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,        —(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or        —(C₁₋₆)alkylene-SO₂—R¹¹;        -   wherein R¹¹ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and        -   wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,            —O(C₁₋₆)alkyl, —O (C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl,            —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —C(═O)—NH₂,            —C(═O)—NH(C₁₋₄)alkyl, —C(═O)—N((C₁₋₄)alkyl)₂, —C(═O)-aryl,            —C(═O)—Het, NH₂, —NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂;        -   ii) (C₁₋₆)alkyl optionally substituted with —OH,            —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and        -   iii) aryl or Het, wherein each of the aryl and Het is            optionally substituted with halo, (C₁₋₆)alkyl or COOH; and    -   c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or        —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰ wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R¹⁰ is in each instance independently selected from R¹¹,            —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and            —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above; or            or R⁵ and R⁶, together with the C to which they are            attached, may be linked to form a 5- or 6-membered            carbocycle or a 4- to 7-membered heterocycle optionally            further containing 1 to 3 heteroatoms each independently            selected from N, O and S, wherein each S heteroatom may,            independently and where possible, exist in an oxidized state            such that it is further bonded to one or two oxygen atoms to            form the groups SO or SO₂;    -   wherein the carbocycle or heterocycle is optionally substituted        with 1 to 3 substituents each independently selected from halo,        (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl,        —OH, —O(C₁₋₆)alkyl, —SH, —S(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and        —N((C₁₋₆)alkyl)₂.-   R⁵-B: In one embodiment, R⁵ is H, halo, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl    or —O(C₁₋₆)alkyl.-   R⁵-C: In one embodiment, R⁵ is H, halo, (C₁₋₄)alkyl or (C₁₋₄)    haloalkyl.-   R⁵-D: In one embodiment, R⁵ is H, halo or (C₁₋₄)alkyl.-   R⁵-E: In one embodiment, R⁵ is F or H.-   R⁵-F: In one embodiment, R⁵ is H, F or CH₃.-   R⁵-G: In one embodiment, R⁵ is H.

Any and each individual definition of R⁵ as set out herein may becombined with any and each individual definition of the Core, c, R², R³,R⁴, R⁶, R⁷ and R⁸ as set out herein.

R⁶:

-   R⁶-A: In one embodiment, R⁶ is selected from:    -   a) (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl, nitro, cyano,        aryl and Het;    -   b) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —SO—R¹¹, —SO₂—R¹¹,        —(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,        —(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,        —(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or        —(C₁₋₆)alkylene-SO₂—R¹¹;        -   wherein R¹¹ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and    -   c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or        —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰ wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R¹⁰ is in each instance independently selected from R¹¹,            —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and            —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above;            wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,            —O(C₁₋₆)alkyl, —O (C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl,            —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and            —N((C₁₋₆)alkyl)₂;        -   ii) (C₁₋₆)alkyl optionally substituted with —OH,            —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and        -   iii) aryl or Het, wherein each of the aryl and Het is            optionally substituted with halo, (C₁₋₆)alkyl or COOH; and-   R⁶ may also be H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl when at    least one of R⁵ or R⁸ is other than H or when R⁷ is other than H,    halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when-   R² is other than H, (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl; or    -   R⁵ and R⁶, together with the C to which they are attached or R⁶        and R⁷, together with the C to which they are attached may be        linked to form a 5- or 6-membered carbocycle or a 4- to        7-membered heterocycle optionally further containing 1 to 3        heteroatoms each independently selected from N, O and S, wherein        each S heteroatom may, independently and where possible, exist        in an oxidized state such that it is further bonded to one or        two oxygen atoms to form the groups SO or SO₂;    -   wherein the carbocycle or heterocycle is optionally substituted        with 1 to 3 substituents each independently selected from halo,        (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl,        —OH, —O(C₁₋₆)alkyl, —SH, —S(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and        —N((C₁₋₆)alkyl)₂.-   R⁶-B: In one embodiment, R⁶ is selected from:    -   a) (C₂₋₆)alkenyl, aryl and Het; and    -   b) —O—(C₁₋₆)alkyl; or    -   R⁶ may also be halo when at least one of R⁵ or R⁸ is other than        H or when R⁷ is other than H, halo, (C₁₋₆)alkyl, or        (C₁₋₆)haloalkyl or when R² is other than H, (C₁₋₆)alkyl, or        —O—(C₁₋₆)alkyl.-   R⁶-C: In one embodiment, R⁶ is H, halo, (C₁₋₆)alkyl or    (C₁₋₆)haloalkyl, when at least one of R⁵ or R⁸ is other than H or    when R⁷ is other than H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or    when R² is other than H, (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl.-   R⁶-D: In another embodiment, R⁶ is CH═CH₂, phenyl, OCH₃; or    -   CH₃, CH₂CH₃, H, F, Cl or Br when at least one of R⁵ or R⁸ is        other than H or when R⁷ is other than H, halo, (C₁₋₆)alkyl, or        (C₁₋₆)haloalkyl or when R² is other than H, (C₁₋₆)alkyl, or        —O—(C₁₋₆)alkyl.-   R⁶-E: In another embodiment, R⁶ is CH═CH₂, phenyl, or OCH₃; or    -   H, Br, CH₃ or CH₂CH₃ when at least one of R⁵ or R⁸ is other than        H or when R⁷ is other than H, halo, (C₁₋₆)alkyl, or        (C₁₋₆)haloalkyl or when R² is other than H, (C₁₋₆)alkyl, or        —O—(C₁₋₆)alkyl.-   R⁶-F: In another embodiment, R⁶ is H when at least one of R⁵ or R⁸    is other than H or when R⁷ is other than H, halo, (C₁₋₆)alkyl, or    (C₁₋₆)haloalkyl or when R² is other than H, (C₁₋₆)alkyl, or    —O—(C₁₋₆)alkyl.-   R⁶-G: In another embodiment, R⁶ is C≡CH, CH═CH₂, phenyl or OCH₃; or    -   H, Br when at least one of R⁵ or R⁸ is other than H or when R⁷        is other than H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when        R² is other than H, (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl.

Any and each individual definition of R⁶ as set out herein may becombined with any and each individual definition of the Core, c, R², R³,R⁴, R⁵, R⁷ and R⁸ as set out herein.

R⁷:

-   R⁷-A: In one embodiment, R⁷ is selected from:    -   a) (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl, nitro, cyano,        aryl and Het;    -   b) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —SO—R¹¹, —SO₂—R¹¹,        —(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,        —(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,        —(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or        —(C₁₋₆)alkylene-SO₂—R¹¹;        -   wherein R¹¹ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and    -   c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,        (C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or        —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰ wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R¹⁰ is in each instance independently selected from R¹¹,            —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and            —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above;            wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,            —O(C₁₋₆)alkyl, —O (C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl,            —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and            —N((C₁₋₆)alkyl)₂;        -   ii) (C₁₋₆)alkyl optionally substituted with —OH,            —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and        -   iii) aryl or Het, wherein each of the aryl and Het is            optionally substituted with halo, (C₁₋₆)alkyl or COOH; and            R⁷ may also be H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl when            at least one of R⁵ or R⁸ is other than H or when R⁶ is other            than H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when R² is            other than H, (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl; or        -   R⁶ and R⁷, together with the C to which they are attached,            or R⁷ and R⁸, together with the C to which they are            attached; may be linked to form a 5- or 6-membered            carbocycle or a 4- to 7-membered heterocycle optionally            further containing 1 to 3 heteroatoms each independently            selected from N, O and S, wherein each S heteroatom may,            independently and where possible, exist in an oxidized state            such that it is further bonded to one or two oxygen atoms to            form the groups SO or SO₂;            wherein the carbocycle or heterocycle is optionally            substituted with 1 to 3 substituents each independently            selected from halo, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, —OH, —O(C₁₋₆)alkyl, —SH,            —NH₂, —NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂.-   R⁷-B: In one embodiment, R⁷ is selected from:    -   a) (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl, nitro, cyano,        aryl and Het;    -   b) —(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-O—R¹¹,        -   wherein R¹¹ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and    -   c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —(C₁₋₆)alkylene-N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰, wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R¹⁰ is in each instance independently selected from R¹¹,            —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and            —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above;            wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,            —O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl,            —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and            —N((C₁₋₆)alkyl)₂;        -   ii) (C₁₋₆)alkyl optionally substituted with —OH,            —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and        -   iii) aryl or Het, wherein each of the aryl and Het is            optionally substituted with halo, (C₁₋₆)alkyl or COOH; or            R⁷ may also be H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl when            at least one of R⁵ or R⁸ is other than H or when R⁶ is other            than H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when R² is            other than H, (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl.-   R⁷-C: In one embodiment, R⁷ is selected from:    -   a) (C₂₋₆)alkenyl, (C₃₋₇)cycloalkyl, nitro, cyano, aryl and Het;    -   b) —(C₁₋₆)alkylene-R¹¹,        -   wherein R¹¹ is in each instance independently selected from            H, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, aryl and Het; and    -   c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R¹⁰ is in each instance independently selected from R¹¹,            —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and            —C(═O)N(R⁶)R¹¹; wherein R¹¹ and R⁹ are as defined above;            wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,            —O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl,            —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and            —N((C₁₋₆)alkyl)₂;        -   ii) (C₁₋₆)alkyl optionally substituted with —OH,            —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and        -   iii) aryl or Het, wherein each of the aryl and Het is            optionally substituted with halo, (C₁₋₆)alkyl or COOH;-   R⁷ may also be H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl when at    least one of R⁵ or R⁸ is other than H or when R⁶ is other than H,    halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when R² is other than H,    (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl.-   R⁷-D: In one embodiment, R⁷ is selected from:    -   a) aryl or Het; and    -   b)-(C₁₋₆)alkylene-R¹¹,        -   wherein R¹¹ is in each instance independently selected from            aryl and Het;            wherein said aryl and Het is optionally substituted with 1            to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, (C₁₋₆)haloalkyl, —OH, —O(C₁₋₆)alkyl,            —O (C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl, —SO(C₁₋₆)alkyl,            —SO₂(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂;            and        -   ii) (C₁₋₆)alkyl.-   R⁷-E: In one embodiment, R⁷ is CH₂OH, CN, OCH₃, CH═CH₂, cyclopropyl,    NH₂, NO₂, CONH₂, NHC(═O)CH₃,

-   R⁷-F: In one embodiment, R⁷ is CH₂OH, CN, OCH₃, CH═CH₂, cyclopropyl,    NH₂, NO₂, CONH₂, NHC(═O)CH₃,

-   -   H, when at least one of R⁵ or R⁸ is other than H or when R⁶ is        other than H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when R²        is other than H, (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl.

-   R⁷-G: In one embodiment, R⁷ is H, when at least one of R⁵ or R⁸ is    other than H or when R⁶ is other than H, halo, (C₁₋₆)alkyl, or    (C₁₋₆)haloalkyl or when R² is other than H, (C₁₋₆)alkyl, or    —O—(C₁₋₆)alkyl.

Any and each individual definition of R⁷ as set out herein may becombined with any and each individual definition of the Core, c, R², R³,R⁴, R⁵, R⁶ and R⁸ as set out herein.

R⁸:

-   R⁸-A: In another embodiment, R⁸ is selected from:    -   a) halo, nitro or cyano;    -   b) R¹¹, —C(═O)—O—R¹¹, —S—R¹¹, —S—R¹¹, —SO—R¹¹, —SO₂—R¹¹,        —(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,        —(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,        —(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or        —(C₁₋₆)alkylene-SO₂—R¹¹;        -   wherein R¹¹ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and        -   wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,            —O(C₁₋₆)alkyl, —O (C₁₋₆)haloalkyl, —SH, —SO(C₁₋₆)alkyl,            —SO₂(C₁₋₆)alkyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄)alkyl,            —C(═O)—N((C₁₋₄)alkyl)₂, —C(═O)-aryl, —C(═O)—Het, NH₂,            —NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂;        -   ii) (C₁₋₆)alkyl optionally substituted with —OH,            —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and        -   iii) aryl or Het, wherein each of the aryl and Het is            optionally substituted with halo, (C₁₋₆)alkyl or COOH; and    -   c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or        —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰ wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R¹⁰ is in each instance independently selected from R¹¹,            —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and            —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above;            -   or R⁷ and R⁸, together with the C to which they are                attached;            -   may be linked to form a 5- or 6-membered carbocycle or a                4- to 7-membered heterocycle optionally further                containing 1 to 3 heteroatoms each independently                selected from N, O and S, wherein each S heteroatom may,                independently and where possible, exist in an oxidized                state such that it is further bonded to one or two                oxygen atoms to form the groups SO or SO₂;        -   wherein the carbocycle or heterocycle is optionally            substituted with 1 to 3 substituents each independently            selected from halo, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, —OH, —O(C₁₋₆)alkyl, —SH,            —S(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂.-   R⁸-B: In another embodiment, R⁸ is selected from:    -   a) halo;    -   b) R¹¹, —O—R¹¹, or —(C₁₋₆)alkylene-R¹¹        -   wherein R¹¹ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl, aryl and            Het; and        -   wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, (C₁₋₆)haloalkyl, —OH, —O(C₁₋₆)alkyl,            —O (C₁₋₆)haloalkyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄) alkyl,            —C(═O)—N((C₁₋₄)alkyl)₂, —C(═O)-aryl, —C(═O)—Het, —NH₂,            —NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂;        -   ii) (C₁₋₆)alkyl; and        -   iii) aryl or Het, wherein each of the aryl and Het is            optionally substituted with halo, (C₁₋₆)alkyl or COOH; and    -   c) —N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,        —(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or        —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰ wherein        -   R⁹ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and    -   R¹⁰ is in each instance independently selected from R¹¹,        —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and        —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above.-   R⁸-C: In another embodiment, R⁸ is selected from:    -   a) halo; and    -   b) H, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, —O—(C₁₋₆)haloalkyl, aryl and        Het, —(C₁₋₆)alkylene-aryl, —(C₁₋₆)alkylene-Het;        -   wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, oxo, thioxo, —O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl,            —C(═O)—NH₂, —C(═O)—NH(C₁₋₄)alkyl, —C(═O)—N((C₁₋₄)alkyl)₂,            —C(═O)-aryl, C(═O)—Het; and        -   ii) (C₁₋₆)alkyl.-   R⁸-D: In another embodiment, R⁸ is selected from:    -   a) F, Cl, Br; and    -   b) H, (C₁₋₃)alkyl, —O—(C₁₋₃)haloalkyl, phenyl and Het,        —(C₁₋₃)alkylene-phenyl, —(C₁₋₃)alkylene-Het;        -   wherein each of the aryl and Het is optionally substituted            with 1 to 2 substituents each independently selected from:        -   i) oxo, thioxo, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄)alkyl,            —C(═O)—N((C₁₋₄)alkyl)₂, —C(═O)-aryl, —C(═O)—Het; and        -   ii) (C₁₋₆)alkyl.-   R⁸-E: In another embodiment, R⁸ is selected from: H, Br, F, CH₃,    CH₂CH₃, OCF₃

-   R⁸-F: In another embodiment, R⁸ is H, Br, F, CH₃, CH₂CH₃ or OCF₃.-   R⁸-G: In another embodiment, R⁸ is selected from:

Any and each individual definition of R⁸ as set out herein may becombined with any and each individual definition of the Core, c, R², R³,R⁴, R⁵, R⁶ and R⁷ as set out herein.

Examples of preferred subgeneric embodiments of the present inventionare set forth in the following table, wherein each substituent group ofeach embodiment is defined according to the definitions set forth above:

Embodiment Core R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ E-1 Core-A R²-I R³-I R⁴-H R⁵-D R⁶-DR⁷-E R⁸-D E-2 Core-A R²-H R³-I R⁴-I R⁵-E R⁶-E R⁷-D R⁸-B E-3 Core-A R²-ER³-I R⁴-J R⁵-F R⁶-F R⁷-F R⁸-G E-4 Core-A R²-I R³-J R⁴-K R⁵-G R⁶-G R⁷-FR⁸-E E-5 Core-A R²-H R³-B R⁴-L R⁵-D R⁶-A R⁷-D R⁸-F E-6 Core-A R²-E R³-CR⁴-H R⁵-D R⁶-G R⁷-D R⁸-G E-7 Core-A R²-H R³-I R⁴-L R⁵-F R⁶-F R⁷-F R⁸-EE-8 Core-A R²-A R³-A R⁴-K R⁵-E R⁶-G R⁷-B R⁸-A E-9 Core-A R²-B R³-D R⁴-HR⁵-F R⁶-D R⁷-C R⁸-C E-10 Core-A R²-C R³-E R⁴-L R⁵-G R⁶-D R⁷-A R⁸-C E-11Core-A R²-D R³-A R⁴-B R⁵-A R⁶-E R⁷-D R⁸-D E-12 Core-A R²-B R³-F R⁴-KR⁵-F R⁶-D R⁷-F R⁸-G E-13 Core-A R²-C R³-E R⁴-L R⁵-G R⁶-E R⁷-G R⁸-E E-14Core-A R²-D R³-B R⁴-J R⁵-C R⁶-F R⁷-B R⁸-G E-15 Core-A R²-E R³-G R⁴-AR⁵-E R⁶-G R⁷-G R⁸-D E-16 Core-A R²-G R³-A R⁴-B R⁵-A R⁶-D R⁷-G R⁸-E E-17Core-A R²-F R³-H R⁴-E R⁵-D R⁶-E R⁷-A R⁸-F E-18 Core-A R²-H R³-C R⁴-DR⁵-B R⁶-F R⁷-G R⁸-B E-19 Core-A R²-I R³-D R⁴-F R⁵-D R⁶-A R⁷-C R⁸-C E-20Core-A R²-I R³-I R⁴-C R⁵-E R⁶-B R⁷-G R⁸-A E-21 Core-A R²-I R³-I R⁴-HR⁵-D R⁶-D R⁷-E R⁸-G E-22 Core-A R²-H R³-I R⁴-H R⁵-D R⁶-D R⁷-E R⁸-G E-23Core-A R²-E R³-I R⁴-H R⁵-D R⁶-D R⁷-E R⁸-G E-24 Core-B R²-I R³-I R⁴-HR⁵-D R⁶-D R⁷-E R⁸-D E-25 Core-B R²-H R³-I R⁴-I R⁵-E R⁶-E R⁷-D R⁸-B E-26Core-B R²-E R³-I R⁴-J R⁵-F R⁶-F R⁷-F R⁸-G E-27 Core-B R²-I R³-J R⁴-KR⁵-G R⁶-G R⁷-F R⁸-E E-28 Core-B R²-I R³-I R⁴-K R⁵-G R⁶-G R⁷-F R⁸-E E-29Core-B R²-I R³-I R⁴-K R⁵-G R⁶-G R⁷-G R⁸-E E-30 Core-B R²-H R³-B R⁴-LR⁵-D R⁶-A R⁷-D R⁸-F E-31 Core-B R²-E R³-C R⁴-H R⁵-D R⁶-G R⁷-D R⁸-G E-32Core-B R²-H R³-I R⁴-L R⁵-F R⁶-F R⁷-F R⁸-E E-33 Core-B R²-I R³-I R⁴-JR⁵-F R⁶-B R⁷-E R⁸-B E-34 Core-B R²-E R³-B R⁴-K R⁵-G R⁶-D R⁷-E R⁸-D E-35Core-B R²-E R³-C R⁴-J R⁵- R⁶-E R⁷-D R⁸-E E-36 Core-B R²-H R³-E R⁴-J R⁵-CR⁶-C R⁷-F R⁸-D E-37 Core-B R²-H R³-F R⁴-I R⁵-D R⁶-F R⁷-F R⁸-B E-38Core-B R²-A R³-A R⁴-K R⁵-E R⁶-G R⁷-B R⁸-A E-39 Core-B R²-B R³-D R⁴-HR⁵-F R⁶-D R⁷-C R⁸-C E-40 Core-B R²-C R³-E R⁴-L R⁵-G R⁶-D R⁷-A R⁸-C E-41Core-B R²-D R³-A R⁴-B R⁵-A R⁶-E R⁷-D R⁸-D E-42 Core-B R²-E R³-J R⁴-CR⁵-B R⁶-A R⁷-F R⁸-B E-43 Core-B R²-F R³-I R⁴-D R⁵-D R⁶-B R⁷-E R⁸-B E-44Core-B R²-G R³-C R⁴-E R⁵-E R⁶-C R⁷-D R⁸-C E-45 Core-B R²-A R³-D R⁴-AR⁵-F R⁶-C R⁷-E R⁸-D E-46 Core-B R²-B R³-F R⁴-K R⁵-F R⁶-D R⁷-F R⁸-G E-47Core-B R²-C R³-E R⁴-L R⁵-G R⁶-E R⁷-G R⁸-E E-48 Core-B R²-D R³-B R⁴-JR⁵-C R⁶-F R⁷-B R⁸-G E-49 Core-B R²-E R³-G R⁴-A R⁵-E R⁶-G R⁷-G R⁸-D E-50Core-B R²-G R³-A R⁴-B R⁵-A R⁶-D R⁷-G R⁸-E E-51 Core-B R²-F R³-H R⁴-ER⁵-D R⁶-E R⁷-A R⁸-F E-52 Core-B R²-H R³-C R⁴-D R⁵-B R⁶-F R⁷-G R⁸-B E-53Core-B R²-I R³-D R⁴-F R⁵-D R⁶-A R⁷-C R⁸-C E-54 Core-B R²-I R³-I R⁴-CR⁵-E R⁶-B R⁷-G R⁸-A E-55 Core-B R²-I R³-I R⁴-H R⁵-D R⁶-D R⁷-E R⁸-G E-56Core-B R²-H R³-I R⁴-H R⁵-D R⁶-D R⁷-E R⁸-G E-57 Core-B R²-E R³-I R⁴-HR⁵-D R⁶-D R⁷-E R⁸-G E-58 Core-C R²-I R³-I R⁴-H R⁵-D R⁶-D R⁷-E R⁸-D E-59Core-C R²-H R³-I R⁴-I R⁵-E R⁶-E R⁷-D R⁸-B E-60 Core-C R²-E R³-I R⁴-JR⁵-F R⁶-F R⁷-F R⁸-G E-61 Core-C R²-H R³-I R⁴-H R⁵-D R⁶-D R⁷-E R⁸-G E-62Core-C R²-E R³-I R⁴-H R⁵-D R⁶-D R⁷-E R⁸-G

Examples of most preferred compounds according to this invention areeach single compound listed in the following Tables 1 to 4.

In general, all tautomeric and isomeric forms and mixtures thereof, forexample, individual tautomers, geometric isomers, stereoisomers,atropisomers, enantiomers, diastereomers, racemates, racemic ornon-racemic mixtures of stereoisomers, mixtures of diastereomers, ormixtures of any of the foregoing forms of a chemical structure orcompound is intended, unless the specific stereochemistry or isomericform is specifically indicated in the compound name or structure.

It is well-known in the art that the biological and pharmacologicalactivity of a compound is sensitive to the stereochemistry of thecompound. Thus, for example, enantiomers often exhibit strikinglydifferent biological activity including differences in pharmacokineticproperties, including metabolism, protein binding, and the like, andpharmacological properties, including the type of activity displayed,the degree of activity, toxicity, and the like. Thus, one skilled in theart will appreciate that one enantiomer may be more active or mayexhibit beneficial effects when enriched relative to the otherenantiomer or when separated from the other enantiomer. Additionally,one skilled in the art would know how to separate, enrich, orselectively prepare the enantiomers of the compounds of the presentinvention from this disclosure and the knowledge in the art.

Preparation of Pure Stereoisomers, e.g. Enantiomers and Diastereomers,or Mixtures of desired enantiomeric excess (ee) or enantiomeric purity,are accomplished by one or more of the many methods of (a) separation orresolution of enantiomers, or (b) enantioselective synthesis known tothose of skill in the art, or a combination thereof. These resolutionmethods generally rely on chiral recognition and include, for example,chromatography using chiral stationary phases, enantioselectivehost-guest complexation, resolution or synthesis using chiralauxiliaries, enantioselective synthesis, enzymatic and nonenzymatickinetic resolution, or spontaneous enantioselective crystallization.Such methods are disclosed generally in Chiral Separation Techniques: APractical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R. P. W. Scott, Chiral Chromatography, John Wiley & Sons,1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am.Chem. Soc., 2000, herein incorporated by reference. Furthermore, thereare equally well-known methods for the quantitation of enantiomericexcess or purity, for example, GC, HPLC, CE, or NMR, and assignment ofabsolute configuration and conformation, for example, CD, ORD, X-raycrystallography, or NMR.

Pharmaceutical Composition

Compounds of the present invention may be administered to a mammal inneed of treatment for HIV infection as a pharmaceutical compositioncomprising a therapeutically effective amount of a compound according tothe invention or a pharmaceutically acceptable salt or ester thereof;and one or more conventional non-toxic pharmaceutically-acceptablecarriers, adjuvants or vehicles. The specific formulation of thecomposition is determined by the solubility and chemical nature of thecompound, the chosen route of administration and standard pharmaceuticalpractice. The pharmaceutical composition according to the presentinvention may be administered orally or systemically.

When one enantiomer of a chiral active ingredient has a differentbiological activity than the other, it is contemplated that thepharmaceutical composition according to the invention may comprise aracemic mixture of the active ingredient, a mixture enriched in oneenantiomer of the active ingredient or a pure enantiomer of the activeingredient. The mixture enriched in one enantiomer of the activeingredient is contemplated to contain from more than 50% to about 100%of one enantiomer of the active ingredient and from about 0% to lessthan 50% of the other enantiomer of the active ingredient. Preferably,when the composition comprises a mixture enriched in one enantiomer ofthe active ingredient or a pure enantiomer of the active ingredient, thecomposition comprises from more than 50% to about 100% of, or only, themore physiologically active enantiomer and/or the less toxic enantiomer.It is well known that one enantiomer of an active ingredient may be themore physiologically active for one therapeutic indication while theother enantiomer of the active ingredient may be the morephysiologically active for a different therapeutic indication; thereforethe preferred enantiomeric makeup of the pharmaceutical composition maydiffer for use of the composition in treating different therapeuticindications.

For oral administration, the compound, or a pharmaceutically acceptablesalt or ester thereof, can be formulated in any orally acceptable dosageform including but not limited to aqueous suspensions and solutions,capsules or tablets. For systemic administration, including but notlimited to administration by subcutaneous, intracutaneous, intravenous,intramuscular, intra-articular, intrasynovial, intrasternal,intrathecal, and intralesional injection or infusion techniques, it ispreferred to use a solution of the compound, or a pharmaceuticallyacceptable salt or ester thereof, in a pharmaceutically acceptablesterile aqueous vehicle.

Pharmaceutically acceptable carriers, adjuvants, vehicles, excipientsand additives as well as methods of formulating pharmaceuticalcompositions for various modes of administration are well-known to thoseof skill in the art and are described in pharmaceutical texts such asRemington: The Science and Practice of Pharmacy, 21st Edition,Lippincott Williams & Wilkins, 2005; and L. V. Allen, N. G. Popovish andH. C. Ansel, Pharmaceutical Dosage Forms and Drug Delivery Systems, 8thed., Lippincott Williams & Wilkins, 2004, herein incorporated byreference.

The dosage administered will vary depending upon known factors,including but not limited to the activity and pharmacodynamiccharacteristics of the specific compound employed and its mode, time androute of administration; the age, diet, gender, body weight and generalhealth status of the recipient; the nature and extent of the symptoms;the severity and course of the infection; the kind of concurrenttreatment; the frequency of treatment; the effect desired; and thejudgment of the treating physician. In general, the compound is mostdesirably administered at a dosage level that will generally affordantivirally effective results without causing any harmful or deleteriousside effects.

A daily dosage of active ingredient can be expected to be about 0.001 toabout 100 milligrams per kilogram of body weight, with the preferreddose being about 0.01 to about 50 mg/kg. Typically, the pharmaceuticalcomposition of this invention will be administered from about 1 to about5 times per day or alternatively, as a continuous infusion. Suchadministration can be used as a chronic or acute therapy. The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Preferably,such preparations contain from about 20% to about 80% active compound.

Therefore, according to one embodiment, the pharmaceutical compositionaccording to the invention comprises a racemic mixture of the compoundof formula (I), or a pharmaceutically acceptable salt or ester thereof.

An alternative embodiment provides a pharmaceutical compositioncomprising a mixture enriched in one enantiomer of the compound offormula (I), or a pharmaceutically acceptable salt or ester thereof.

A further embodiment provides a pharmaceutical composition comprising apure enantiomer of the compound of formula (I), or a pharmaceuticallyacceptable salt or ester thereof.

Combination Therapy

Combination therapy is contemplated wherein a compound according to theinvention, or a pharmaceutically acceptable salt or ester thereof, isco-administered with at least one additional antiviral agent. Theadditional agents may be combined with compounds of this invention tocreate a single dosage form. Alternatively these additional agents maybe separately administered, concurrently or sequentially, as part of amultiple dosage form.

When the pharmaceutical composition of this invention comprises acombination of a compound according to the invention, or apharmaceutically acceptable salt or ester thereof, and one or moreadditional antiviral agent, both the compound and the additional agentshould be present at dosage levels of between about 10 to 100%, and morepreferably between about 10 and 80% of the dosage normally administeredin a monotherapy regimen. In the case of a synergistic interactionbetween the compound of the invention and the additional antiviral agentor agents, the dosage of any or all of the active agents in thecombination may be reduced compared to the dosage normally administeredin a monotherapy regimen.

Antiviral agents contemplated for use in such combination therapyinclude agents (compounds or biologicals) that are effective to inhibitthe formation and/or replication of a virus in a mammal, including butnot limited to agents that interfere with either host or viralmechanisms necessary for the formation and/or replication of a virus ina mammal. Such agents can be selected from:

-   -   NRTIs (nucleoside or nucleotide reverse transcriptase        inhibitors) including but not limited to zidovudine (AZT),        didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine        (3TC), emtricitabine, abacavir succinate, elvucitabine, adefovir        dipivoxil, lobucavir (BMS-180194) lodenosine (FddA) and        tenofovir including tenofovir disoproxil and tenofovir        disoproxil fumarate salt, COMBIVIR™ (contains 3TC and AZT),        TRIZIVIR™ (contains abacavir, 3TC and AZT), TRUVADA™ (contains        tenofovir and emtricitabine), EPZICOM™ (contains abacavir and        3TC);    -   NNRTIs (non-nucleoside reverse transcriptase inhibitors)        including but not limited to nevirapine, delaviradine,        efavirenz, etravirine and rilpivirine;    -   protease inhibitors including but not limited to ritonavir,        tipranavir, saquinavir, nelfinavir, indinavir, amprenavir,        fosamprenavir, atazanavir, lopinavir, darunavir (TMC-114),        lasinavir and brecanavir (VX-385);    -   entry inhibitors including but not limited to        -   CCR5 antagonists (including but not limited to maraviroc,            vicriviroc, INCB9471 and TAK-652),        -   CXCR4 antagonists (including but not limited to AMD-11070),        -   fusion inhibitors (including but not limited to enfuvirtide            (T-20), TR1-1144 and TR1-999) and        -   others (including but not limited to BMS-488043);    -   integrase inhibitors (including but not limited to raltegravir        (MK-0518), BMS-707035 and elvitegravir (GS 9137));    -   TAT inhibitors;    -   maturation inhibitors (including but not limited to berivimat        (PA-457));    -   immunomodulating agents (including but not limited to        levamisole); and    -   other antiviral agents including hydroxyurea, ribavirin, IL-2,        IL-12 and pensafuside.

Furthermore, a compound according to the invention can be used with atleast one other compound according to the invention or with one or moreantifungal or antibacterial agents (including but not limited tofluconazole).

Therefore, according to one embodiment, the pharmaceutical compositionof this invention additionally comprises one or more antiviral agents.

A further embodiment provides the pharmaceutical composition of thisinvention wherein the one or more antiviral agent comprises at least oneNNRTI.

According to another embodiment of the pharmaceutical composition ofthis invention, the one or more antiviral agent comprises at least oneNRTI.

According to yet another embodiment of the pharmaceutical composition ofthis invention, the one or more antiviral agent comprises at least oneprotease inhibitor.

According to still another embodiment of the pharmaceutical compositionof this invention, the one or more antiviral agent comprises at leastone entry inhibitor.

According to a further embodiment of the pharmaceutical composition ofthis invention, the one or more antiviral agent comprises at least oneintegrase inhibitor.

A compound according to the present invention may also be used as alaboratory reagent or a research reagent. For example, a compound of thepresent invention may be used as positive control to validate assays,including but not limited to surrogate cell-based assays and in vitro orin vivo viral replication assays.

Furthermore, a compound according to the present invention may be usedto treat or prevent viral contamination of materials and thereforereduce the risk of viral infection of laboratory or medical personnel orpatients who come in contact with such materials (e.g. blood, tissue,surgical instruments and garments, laboratory instruments and garments,and blood collection apparatuses and materials).

Derivatives Comprising a Detectable Label

Another aspect of the invention provides a derivative of a compound offormula (I), the derivative comprising a detectable label. Such a labelallows recognition either directly or indirectly of the derivative suchthat it can be detected, measured or quantified. The detectable labelmay itself be detectable, measurable or quantifiable, or it may interactwith one or more other moities which themselves comprise one or moredetectable labels, so that the interaction therebetween allows thederivative to be detected, measured or quantified.

Such derivatives may be used as probes to study HIV replication,including but not limited to study of the mechanism of action of viraland host proteins involved in HIV replication, study of conformationalchanges undergone by such viral and host proteins under variousconditions and study of interactions with entities which bind to orotherwise interact with these viral and host proteins. Derivativesaccording to this aspect of the invention may be used in assays toidentify compounds which interact with viral and host proteins, theassays including but not limited to displacement assays which measurethe extent to which the derivative is displaced from interacting withthe viral and host proteins. A preferred use of derivatives according tothis aspect of the invention is in assays to identify HIV integraseinhibitors. Such derivatives may also be used to form covalent ornon-covalent interactions with the viral and host proteins or toidentify residues of the viral and host proteins which interact with thecompounds of the invention.

Detectable labels contemplated for use with derivatives of the compoundsof the invention include, but are not limited to, fluorescent labels,chemiluminescent labels, chromophores, antibodies, enzymatic markers,radioactive isotopes, affinity tags and photoreactive groups.

A fluorescent label is a label which fluoresces, emitting light of onewavelength upon absorption of light of a different wavelength.Fluorescent labels include but are not limited to fluorescein; TexasRed; aminomethylcoumarin; rhodamine dyes, including but not limited totetramethylrhodamine (TAMRA); Alexa dyes including but not limited toAlexa Fluor® 555; cyanine dyes including but not limited to Cy3;europium or lanthanide series based fluorescent molecules; and the like.

A chemiluminescent label is a label which can undergo a chemicalreaction which produces light. Chemiluminescent labels include but arenot limited to luminol, luciferin, lucigenin, and the like.

A chromophore is a label which selectively absorbs certain wavelengthsof visible light while transmitting or reflecting others, therebycausing the compounds which contain the chromophore to appear colored.Chromophores include but are not limited to natural and synthetic dyes.

An antibody is a protein produced by a mammalian immune system inresponse to a specific antigen, which binds specifically to thatantigen. Antibodies contemplated for use as detectable labels accordingto the invention include but are not limited to antibodies against thefollowing: polyhistidine tags, glutathione-5-transferase (GST),hemagglutinin (HA), FLAG® epitope tags, Myc tag, maltose binding protein(MBP), green fluorescent protein (GFP) and the like.

An enzymatic marker is an enzyme whose presence may be detected by meansof an assay specific to the catalytic activity of the enzyme. Enzymaticmarkers contemplated for use as detectable labels according to theinvention include but are not limited to luciferase, horseradishperoxidase (HRP), β-galactosidase and the like.

A radioactive isotope is an isotope of an atom which produces radiationupon radioactive decay. Radioactive isotopes include but are not limitedto ¹⁴C, ³H, ³¹P, ¹²¹I, ¹²⁵I, and the like.

An affinity tag is a label which has a strong affinity for anothermoiety, designated herein as a binding partner. Such an affinity tag canbe used to form a complex with the binding partner so that the complexmay be selectively detected or separated from a mixture. Affinity tagsinclude but are not limited to biotin or a derivative thereof, ahistidine polypeptide, a polyarginine, an amylose sugar moiety or adefined epitope recognizable by a specific antibody; suitable epitopesinclude but are not limited to glutathione-S-transferase (GST),hemagglutinin (HA), FLAG® epitope tags, Myc tag, maltose binding protein(MBP), green fluorescent protein (GFP) and the like.

Furthermore, compounds of the invention used as probes may be labelledwith a photoreactive group which is transformed, upon activation bylight, from an inert group to a reactive species, such as a freeradical. Such a group may be used to activate the derivative so that itcan form a covalent bond with one or more residues of a viral or hostprotein. Photoreactive groups include but are not limited tophotoaffinity labels such as benzophenone and azide groups.

Methodology and Synthesis

The synthesis of compounds of formula (I) according to this invention isconveniently accomplished following the general procedure outlined inthe schemes below wherein R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as definedherein. Further instruction is provided to one skilled in the art by thespecific examples set out herein below.

wherein R⁴², R⁴³, R⁴⁴, R⁴⁵, and R⁴⁶ may either be substituents on thephenyl moiety or (R⁴² and R⁴³), (R⁴³ and R⁴⁴), (R⁴⁴ and R⁴⁵) or (R⁴⁵ andR⁴⁶) may be linked so to as to form a carbocycle or heterocycle, W isiodo, bromo, chloro or OTf, Y is B(OH)₂ or boronate esters such asB(OCH₃)₂ and B(OC(CH₃)₂C(CH₃)₂O), iodo, SnR₃ wherein R is (C₁₋₆)alkyl,ZnX wherein X is halo, and P is a protecting group, such as commonlyused protecting groups for carboxylic acids, including, but not limitedto a methyl or ethyl ester.

Several coupling methods between the intermediate (I) (i.e. quinolinescaffold) and the intermediate II (i.e. R⁴ substituent) can becontemplated by those skilled in the art. For examples, but not limitedto, Suzuki cross-coupling between the boronic acid or boronate esterderivative of intermediate II and the halo or triflate derivative ofintermediate I, copper catalyzed Ullmann cross-coupling between the iododerivatives of intermediates I and II, Negishi cross-coupling betweenthe arylzinc reagent of the intermediate II and the iodo or triflatederivative of intermediate I, and Stille coupling between the arylltinreagent of II and the bromo or iodo derivative of intermediate I asshown above can lead, after saponification, to the compounds of formula(I).

Alternatively, the same cross-coupling methods can be used byinterchanging the coupling partners as shown below. For examples,Suzuki, Negishi, and Stille type cross-coupling between boronic acid orboronate ester derivative, the arylzinc reagent or the arylltin reagentof quinoline intermediate III and the required iodo, bromo, chloro ortriflate derivative of intermediate IV can also lead, aftersaponification, to the compounds of the invention of formula (I).

wherein R⁴², R⁴³, R⁴⁴, R⁴⁵ and, R⁴⁶ and P are as defined above and W isiodo, bromo, chloro or OTf, Y is B(OH)₂ or boronate esters such asB(OCH₃)₂ and B(OC(CH₃)₂C(CH₃)₂O), SnR₃ wherein R is (C₁₋₆)alkyl, and ZnXwherein X is halo.

Furthermore, downstream modifications to the product can becontemplated, such as conversion of an aniline-type amine to a chloro orbromo substituent via Sandmeyer reaction or alkylation, ordehalogenation via reduction.

Additionally, intermediate III can be used for decarboxylative biarylcross-coupling reactions similar to those described by Forgione,Bilodeau and coworkers, J. Am. Chem. Soc. 2006, 128, 11350-11351, hereinincorporated by reference, as shown below:

wherein W is iodo, bromo, chloro or OTf, R may be a substituent on thering and P is as defined herein.

There are a number of transformations known to access quinolinescaffolds. As shown in Scheme 1A, a Friedlander approach can be followedin which appropriately substituted aniline is condensed with afunctionalized ketone under dehydration conditions. This intermediate isthen cyclized under thermal conditions followed by halogenation of theresulting alcohol. The acetic acid ester side chain can be oxidized andprotected to furnish the alpha t-butoxy acetic acid ester moiety asshown. Separation of the enantiomers can be accomplished by formation ofdiastereomers by addition of a chiral auxiliary such as an oxazolidinonefollowed by conversion to the corresponding ester by known means.

Alternatively, a modification of this approach can also be used toprepare the quinoline scaffold as is shown in Scheme 2. In this method aproperly substituted anthranilic acid derivative can be condensed underdehydration conditions with an appropriate ketone and subsequentlycyclized under DMAP/POCl₃ conditions to the 4-chloroquinoline. Furtherelaboration can then be performed as outlined in Scheme 1A.

Furthermore, in an alternative route the quinoline scaffold can beaccessed in an enantioselective manner as outlined in Scheme 3.

A quinoline precursor can be selectively brominated in the 3-positionand subsequently elaborated into the chiral diol by standard methodsknown in the literature. The chiral diol can be differentially protectedto the t-butyl ether followed by liberation of the primary alcohol. Thisalcohol can then be oxidized to the corresponding carboxylic acid andsubsequently protected as the methyl ester to furnish the key chiral4-iodoquinoline intermediate.

In an alternate route to compounds of general formula I wherein R² is(C₁₋₆)alkyl or —O—C₁₋₆)alkyl, the known aldehyde VIa is transformed toterminal alkyne VIb. Those skilled in the art will recognize that thereare a number of methods for accomplishing this transformation, such as,but not limited to the Bestmann-Ohira reaction or the Corey-Fuchsreaction. The R⁴ group is then attached to the alkyne using conditionswell-known to those skilled in the art, preferentially via a Sonogashiracoupling between the alkyne and the aryl iodide derivative of the R⁴group, to give the internal alkyne VIc. Other methods may include theCastro-Stevens reaction, or the silver mediated, palladium catalyzedcoupling of alkyne VIb and the boronic acid or ester derivative of theR⁴ fragment as reported by Zou and coworkers (Tetrahedron Lett. 2003,44, 8709-8711). The internal alkyne VIc then undergoes acyclocondensation with amide VId to give quinoline VIe. Those skilled inthe art will recognize this may involve activation of amide VId tofacilitate the overall condensation. This is preferentially achieved bythe action of triflic anhydride and in the presence of 2-chloropyridineas described by Movassaghi (J. Am. Chem. Soc., 129 (33), 10096-10097,2007), but may also be achieved in other ways. Amides VId are typicallycommercially available, although those skilled in the art will recognizethat they are also easily obtained from commercially available anilineor nitro arene precursors.

The cyclic diketal is then hydrolyzed to give diol VIf under acidicconditions. The terminal alcohol is then protected to give VIg, where Pcan be a number of different protecting groups including, but notlimited to, a trimethylacetyl group. The secondary alcohol is thenderivatized with a tert-butyl group to give compound VIh. Those skilledin the art will recognize that this can be accomplished in more than oneway, including an SN₁ reaction or acid catalyzed addition toisobutylene. The protecting group is then removed to give primaryalcohol VIj, which in turn is oxidized to carboxylic acid VIk. It willbe obvious that the oxidation of VIj to VIk can be accomplished in oneor two synthetic steps. In the preferred method, Dess-Martin oxidationto an intermediate aldehyde followed by Lindgren oxidation is employed.

In yet another route to compounds of general formula I, wherein R² is(C₁₋₆)alkyl or —O—C₁₋₆)alkyl, synthesis of intermediate VIh may also beaccomplished following a path that begins with acid catalyzed hydrolysisof the cyclic diketal of terminal alkyne VIb to give diol VIIa. Theterminal alcohol is then protected to give VIIb, where P can be a numberof different protecting groups including, but not limited to, atrimethylacetyl group. The secondary alcohol is then derivatized withthe tert-butyl group to give compound VIIc. Those skilled in the artwill recognize that this can be accomplished in more than one way,including an SN₁ reaction or acid catalyzed addition to isobutylene. TheR⁴ group is then attached to the alkyne using conditions well-known tothose skilled in the art, preferentially via a Sonogashira couplingbetween the alkyne and the aryl iodide derivative of the R⁴ group, togive the internal alkyne VIId. The internal alkyne VIId then undergoes acyclocondensation with amide VId to give quinoline VIh, preferentiallyachieved by the action of triflic anhydride and in the presence of2-chloropyridine as described for step 3 of Scheme 4. From intermediateVIh, the synthesis of compounds of general formula I is thenaccomplished following steps 7 and 8 of Scheme 4.

EXAMPLES

Other features of the present invention will become apparent from thefollowing non-limiting examples which illustrate, by way of example, theprinciples of the invention. It will be apparent to a skilled personthat the procedures exemplified below may be used, with appropriatemodifications, to prepare other compounds of the invention as describedherein.

As is well known to a person skilled in the art, reactions are performedin an inert atmosphere (including but not limited to nitrogen or argon)where necessary to protect reaction components from air or moisture.Temperatures are given in degrees Celsius (° C.). Solution percentagesand ratios express a volume to volume relationship, unless statedotherwise. Flash chromatography is carried out on silica gel (SiO₂)according to the procedure of W. C. Still et al., J. Org. Chem., (1978),43, 2923. Mass spectral analyses are recorded using electrospray massspectrometry. A number of intermediate and final products were arepurified using CombiFlash® Companion apparatus, purchased from TeledyneIsco Inc, employing pre-packed silica gel cartridges and EtOAc andhexane as solvents. These cartridges are available either from SilicycleInc (SiliaFlash, 40-63 microns silica) or from Teledyne Isco (RediSep,40-63 microns silica). Preparative HPLC is carried out under standardconditions using a SunFire™ Prep C18 OBD 5 μM reverse phase column,19×50 mm and a linear gradient employing 0.1% TFA/acetonitrile and 0.1%TFA/water as solvents. Compounds are isolated as TFA salts whenapplicable. Analytical HPLC is carried out under standard conditionsusing a Combiscreen ODS-AQ C18 reverse phase column, YMC, 50×4.6 mmi.d., 5 μM, 120 Å at 220 nM, elution with a linear gradient as describedin the following table (Solvent A is 0.06% TFA in H₂O; solvent B is0.06% TFA in CH₃CN):

Time (min) Flow (mL/min) Solvent A (%) Solvent B (%) 0 3.0 95 5 0.5 3.095 5 6.0 3.0 50 50 10.5 3.5 0 100

Abbreviations or symbols used herein include:

Ac: acetyl; AcOH: acetic acid; Ac₂O: acetic anhydride; BOC or Boc:tert-butyloxycarbonyl; Bu: butyl; DABCO: 1,4-diazabicyclo[2.2.2]octaneDBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCE: dichloroethane; DEAD:diethyl azodicarboxylate DCM: dichloromethane; DIAD: diisopropylazodicarboxylate; DIBAL: diisobutyl aluminum hydride; DIPEA:diisopropylethylamine; DMAP: N,N-dimethyl-4-aminopyridine; DME:1,2-dimethoxyethane; DMF: N,N-dimethylformamide; DMSO:dimethylsulfoxide; Dppf: 1,1′-Bis(diphenylphosphino)ferrocene; EC₅₀: 50%effective concentration; Et: ethyl; Et₃N : triethylamine; Et₂O: diethylether; EtOAc: ethyl acetate; EtOH: ethanol; HATU:O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetra- methyluroniumhexafluorophosphate; HBTU: O-Benzotriazole-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HPLC: high performance liquid chromatography; IC₅₀:50% inhibitory concentration; ^(i)Pr or i-Pr: 1-methylethyl(iso-propyl); KHMDS: potassium hexamethyl disilazane; LiHMDS: lithiumhexamethyldisilazide; Me: methyl; MeCN: acetonitrile; MeOH: methanol;MOI: multiplicity of infection; MS: mass spectrometry (ES:electrospray); n-BuONa: sodium n-butoxide n-BuOH: n-butanol; n-BuLI:n-butyllithium; NMO: N-methylmorpholine-N-oxide; NMR: nuclear magneticresonance spectroscopy; Ph: phenyl; PhMe: toluene; PG: protecting group;PPh₃: triphenylphosphine; Pr: propyl; RPMI: Roswell Park MemorialInstitute (cell culture medium); RT: room temperature (approximately 18°C. to 25° C.); SM: starting material; tert-butyl or 1,1-dimethylethyl;t-butyl: Tf: trifluoromethanesulfonyl; Tf₂O: trifluoromethanesulfonicanhydride; TFA: trifluoroacetic acid; THF: tetrahydrofuran; and TLC:thin layer chromatography.

Example 1 Synthesis of Quinoline Scaffold 1i

Step 1:

In a 4-neck 500 mL round bottom flask equipped with a magnetic stir bar,condenser and Dean-Stark trap, diethyl acetylsuccinate (6 g, 0.026 mol),aniline 1a (2.5 mL, 0.028 mol), Amberlyst® 15 (0.08 g) and toluene (30mL) are added. The resulting mixture is heated at reflux temperature forapproximately 3 days at which time TLC showed only traces of SM. Thereaction mixture is cooled to RT and the Amberlyst® 15 is removed byfiltration. The filtrate is concentrated in vacuo to give a suspensionof a solid in brown liquid. The filtrate is diluted with diethyl etherand cooled. The solid is filtered and the filtrate is concentrated invacuo leaving a brown oil (˜7.8 g), which contains 1b and some cyclisedintermediate. This crude intermediate is used in the next step withoutfurther purification.

Step 2:

In a 3-neck 100 mL round bottom flask a mixture of the crudeintermediate 1b (7.8 g) and diphenyl ether (50 mL) are heated quickly ina pre-heated (250° C.) heating mantle for 6 min (internal temperaturereached ˜250° C.) at which time the flask is removed from the heatingmantle and is stirred until the internal temperature reaches below 100°C. The reaction mixture is then mixed with hexane (15 mL), at which timea light brown solid is formed. The solid is filtered and washed withhexane (3×10 mL) to give approximately 2.4 g of the intermediatecyclised product. A portion of this sample (1.4 g, 5.87 mmol) isdissolved in phosphorus oxychloride (5 mL) and heated at reflux for 2.5h. The reaction mixture is cooled to RT and is concentrated on vacuum.The residue is treated with sodium bicarbonate powder then partitionedbetween EtOAc and water. The combined organic layer is washed withbrine, dried over anhydrous Na₂SO₄, filtered, passed through a silicagel pad and concentrated to give 1c as a crude light brown solid (2.35g).

Step 3:

Crude chloro quinoline 1c (1.36 g, 5.17 mmol) is dissolved in THF (20mL), and HCl in dioxane (4 M, 5.4 mL, 0.022 mol) is added to thissolution slowly. The resulting reaction mixture is stirred at RT for 40min. The solvent is then removed in vacuo and the residue is dried onvacuum. The resulting solid and NaI (3.87 g) are suspended in MeCN (20mL), and the resulting reaction mixture is heated to reflux for 16 h.The reaction mixture is cooled to RT and treated with a saturatedaqueous solution of NaHCO₃ (20 mL). The aqueous layer is extracted withDCM, and the combined organic layer is dried over anhydrous MgSO₄,filtered and concentrated to give a brown syrup. Purification by silicagel chromatography (30% EtOAc/hexanes) provides iodo quinoline 1d as anoff-white solid (1.72 g, 94% yield).

Step 4:

To a solution of KHMDS (0.5 M in toluene, 3 mL, 1.5 mmol) in THF (8 mL)at −78° C. is added a solution of 1d (0.35 g, 0.99 mmol) in THF (8 mL).As the ester is added, the solution becomes a scarlet red. This isallowed to stir at −78° C. for 30 min before being treated with theDavis reagent (0.39 g, 1.5 mmol). After addition of the oxidizing agent,the solution becomes pale yellow and is stirred for an additional 30 minat −78° C. The reaction is quenched with saturated NH₄Cl aqueoussolution (8 mL), is warmed to RT and is diluted with EtOAc. The mixtureis washed with brine and the organic phase dried (Na₂SO₄), filtered andconcentrated to afford a solid. Purification by silica gelchromatography (hexanes/EtOAc:6/4) provides 1e as a beige solid (0.50g, >98% yield).

Step 5:

To a suspension of iodoalcohol 1e (0.53 g, 1.4 mmol) in tert-butylacetate (12 mL) at RT is added perchloric acid (0.66 mL, 4.6 mmol). Thereaction is left to stir for 2 h at RT (suspension turns into a clearsolution). The reaction is quenched with water (12 mL) and basified withsolid NaHCO₃ until pH ˜6. The crude product is extracted with EtOAc(3×10 mL), washed with brine (1×10 mL), dried over MgSO₄, filtered andconcentrated to afford the crude product. Purification by silica gelchromatography (hexanes/EtOAc:85/15) affords 1f as a pale yellow oil(0.56 g, 91% yield).

Step 6:

Intermediate 1f (0.59 g, 1.4 mmol) is dissolved in a 2 M NaOH aqueoussolution (7 mL, 0.014 mol) with ethanol (10 mL) and is stirred for 4 hat RT. The ethanol is then removed in vacuo. The resulting residue isdiluted with water (3 mL) and acidified with 2 M HCl solution until pH˜3-4. The residue is then extracted with CH₂Cl₂ (3×10 mL), dried overNa₂SO₄, filtered, concentrated and dried under high vacuum to afford 1gas a foamy solid (0.56 g, >98% yield).

Step 7:

To a solution of acid 1g (0.39 g, 0.97 mmol) and HBTU (0.48 g, ˜1.3mmol) in anhydrous THF (5 mL) is added diisopropylethylamine (0.5 mL,2.9 mmol). The mixture is stirred for 5.5 h at 30-35° C. (internaltemperature) at which time the sodium salt of R-(+)-benzyloxazolidinone(which is prepared by adding sodium hydride (60% dispersion in mineraloil, 78 mg, 1.95 mmol) to a solution of R-(+)-benzyloxazolidinone (0.35g, 1.9 mmol) in anhydrous THF (5 mL) is added. The resulting solution isthen stirred at RT for 16 h. The solvent is removed in vacuo andpartitioned between water and EtOAc. The aqueous phase is then extractedwith EtOAc, and the combined organic extracts are dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo to afford a pale yellowsolid. The crude product is purified by silica gel chromatography(10->30% EtOAc:hexanes), yielding the desired diastereomer 1 h (190 mg,35% yield, more polar product, >99% ee by chiral column).

Step 8:

To a solution of oxazolidinone 1 h (190 mg, 0.34 mmol) in THF/H₂O (2mL/1 mL) at 0° C. is added H₂O₂ (30%, 0.36 mL, 10.5 eq) followed by LiOHmonohydrate (17 mg, 0.41 mmol, 1.2 eq) dissolved in water (1 mL). Thereaction mixture is stirred at 0° C. for 30 min at which time 10% Na₂SO₃(0.26 mL) is added. The resulting mixture is stirred for ˜10 min andthen acidified with 2 N HCl to pH ˜4-5. The product is then extractedwith DCM (3×10 mL). The combined organic extracts are dried over sodiumsulfate and concentrated in vacuo to yield the crude acid intermediateas a white foam (0.13 g, 96% yield), which is used in the next stepwithout further purification. The acid (130 mg) is suspended in diethylether (3 mL) and treated with diazomethane in diethyl ether until all ofthe acid SM is consumed (as indicated by TLC). The reaction is quenchedwith a very small amount of glacial AcOH and then concentrated in vacuoto give an off-white solid. The crude ester product is purified bysilica gel chromatography (10-15% EtOAc/hexanes) yielding the quinolinefragment 1i (120 mg, 89% yield) in high enantiomeric purity (>99% ee bychiral HPLC).

Example 2 Synthesis of Fragment 2f

Step 1:

Aldehyde 2a (5.85 g, 28.6 mmol, for preparation see: Michel, P. and Ley,S. V. Synthesis 2003, 10, 1598-1602), phoshonate 2b (6.6 g, 34 mmol) andK₂CO₃ (8.8 g, 64 mmol) are combined in MeOH (125 mL) and the reaction isstirred overnight at RT. The reaction is evaporated nearly to drynessand the residue is partitioned between H₂O (250 mL) and EtOAc (500 mL).The water layer is washed with EtOAc (2×250 mL) and the combined organiclayers dried over anhydrous Na₂SO₄ and concentrated to give alkyne 2c(5.55 g, 97% yield).

Step 2:

Alkyne 2c (5.0 g, 25 mmol) is dissolved in TFA (35 mL) and water (3.6mL) and the solution is stirred at RT. After 30 min, the reaction isconcentrated under reduced pressure and the residue is purified byCombiFlash® Companion to give diol 2d (1.8 g, 84% yield).

Step 3:

A solution of diol 2d (1.2 g, 14 mmol) and triethylamine (1.7 mL, 12mmol) in DCM (80 mL) is cooled to 0° C. under N₂.Trimethylacetylchloride is added dropwise and the resulting mixture isallowed to come to RT and stir overnight. The reaction is then quenchedwith MeOH (100 mL) and stirring is continued for 20 min. The mixture isthen concentrated under reduced under pressure and the residue ispurified by CombiFlash® Companion to give the desired mono ester 2e (550mg, 40% yield) along with the undesired regioisomeric mono ester (378mg, 27% yield).

Step 4:

In a sealable reaction flask, a solution of the propargylic alcohol 2e(375 mg, 2.20 mmol) and Amberlyst® H-15 resin (150 mg) in hexane (3 mL)is cooled to −78° C. Isobutene is then bubbled through the solutionuntil the volume approximately doubles. The tube is then sealed, broughtto RT and is stirred overnight. The tube is then cooled to −78° C., isopened and brought back to RT. The mixture is then filtered through aplug of SiO₂ (EtOAc wash) and concentrated under reduced pressure toprovide pure tent-butyl ether 2f (390 mg, 78% yield).

Example 3 Synthesis of Alkyne 3a

Step 1:

Solid Pd(PPh₃)₄ (444 mg, 0.385 mmol) and CuI (146 mg, 0.769 mmol) aresuccessively added to a solution of 11c (10 g, 34 mmol) and alkyne 2c(11 g, 55 mmol) dissolved in DMF (23 mL) and diethylamine (115 mL). Thereaction mixture is stirred overnight at RT and then concentrated,diluted with EtOAc (300 mL) and successively washed with brine, 1 Naqueous HCl and water (300 mL each). The organic layer is dried overNa₂SO₄ and the residue purified by CombiFlash® Companion to give alkyne3a (10.8 g, 84% yield).

Example 4 Synthesis of Boronate Fragment 4f

Step 1:

To a solution of 4a (6 g, 37 mmol) in nitrobenzene (12 mL), chloroacetylchloride (4.6 mL, 57.5 mmol) is added, followed by the addition of AlCl₃(20.4 g, 152 mmol). As the AlCl₃ is added, the mixture becomes viscousand gas evolution is observed. The resulting brown syrupy mixture isleft to stir overnight at RT. (Reference: Y. Takeuchi et. al., Chem.Pharm. Bull. 1997, 45(12), 2011-2015.) The thick reaction mixture iscooled and ice water is added very carefully (Very exothermic) a fewdrops at a time. Once gas evolution and bubbling is subsided, cold wateris further added followed by EtOAc. The mixture is stirred for 5 min andthe product extracted with EtOAc (3×). The combined organic layers arewashed with brine (1×), dried over Na₂SO₄, filtered and concentrated toafford the uncyclized chloroketone (24 g of crude; contaminated withsome nitrobenzene) as a pale yellow solid. This intermediate is thentaken up in EtOH (100 mL), NaOAc is added (20.4 g, 248 mmol) and thereaction is brought to reflux for 40 min. The EtOH is evaporated, theresidue is taken up in EtOAc (300 mL) and washed with 5% K₂CO₃ (2×200mL) and the aqueous layer then acidified with aqueous HCl (1 N; pH=˜5).This acidic layer is extracted with EtOAc (2×250 mL), washed with brine(1×), dried over Na₂SO₄, filtered and concentrated to afford the crudeproduct. This material is purified by CombiFlash® Companion (120 g) toafford intermediate 4b as a yellow solid (4.7 g).

Step 2:

The ketone 4b (127 mg, 0.64 mmol) is dissolved in EtOH (2 mL) andtreated with hydrazine hydrate (500 μL, 16 mmol). The mixture is heatedto reflux for 45 min before allowing it to cool to RT. The solvent isremoved by evaporation and the residue is dissolved in diethylene glycol(1 mL) before being treated with KOH (108 mg, 1.92 mmol) and then heatedto 110-120° C. for 2.5 h. The reaction mixture is diluted with EtOAc andthe pH is adjusted with 1 N HCl to pH<4. The organic phase is separated,washed with saturated brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude material is purified by CombiFlash® Companion(eluent: 0-50% EtOAc/hexanes) to give intermediate 4c as a yellow oil(62 mg).

Step 3:

A solution of 4c (61 mg, 0.33 mmol) is cooled to −78° C. in DCM (2 mL)and then treated with BBr₃ (1 M in DCM, 825 μL, 0.82 mmol). After ˜15min, the bath is removed and the reaction is allowed to reach RT. Thereaction is then stirred for 1.5 h. The reaction is cooled to 0° C.before quenching by the careful dropwise addition of water. The mixtureis treated with saturated NaHCO₃ (to about pH=8) and the phasesseparated. The organic phase is washed with saturated brine, dried overMgSO₄, filtered and concentrated to dryness. The product is purified byCombiFlash® Companion (0-50% EtOAc/hexanes) to give intermediate 4d ascolorless oil, which solidifies upon standing (40 mg, 71% yield).

Step 4:

The phenol 4d (40 mg, 0.23 mmol) is dissolved in DCM (2 mL), cooled to0° C. and treated with pyridine (95 μL, 1.17 mmol), followed by Tf₂O (44μL, 0.26 mmol). The reaction is allowed to stir at this temperature for10 min before warming to RT over a period of 1 h. The reaction mixtureis diluted with DCM and the organic phase washed with 10% citric acidand then brine. The organic phase is dried over anhydrous MgSO₄,filtered, concentrated and purified by CombiFlash® Companion (0-50%EtOAc/hexanes) to give 4e as a yellow oil (67 mg, 94% yield).

Step 5:

To a solution of the triflate 4e (66 mg, 0.22 mmol) in DMF (2 mL),bis-(pinacolato)diborane (72 mg, 0.28 mmol) and potassium acetate (64mg, 0.65 mmol) are added. This solution is de-gassed (with bubbling Ar)for 10 min before adding PdCl₂(dppf)-CH₂Cl₂, (27 mg, 0.03 mmol, 0.15eq). The mixture is de-gassed a further 5 min before being heated to 90°C. for 16 h. The mixture is cooled to RT and diluted with EtOAc/water.The organic phase is washed with saturated brine (3×), dried overanhydrous MgSO₄, filtered and concentrated. The crude material ispurified by CombiFlash® Companion (0-70% EtOAc in hexanes) to afford theboronate 4f as a white solid (41 mg, 67% yield).

Example 5 Synthesis of Boronate Fragment 5f

Step 1:

The nitrophenol 5a (5.23 g, 34.1 mmol) is dissolved in acetic acid (20mL) and the solution is cooled in an ice bath. Bromine (1.75 mL, 34.15mmol) dissolved in 5 mL acetic acid) is added dropwise with stirring.The mixture is stirred for 1 h at 0° C. before being poured into icewater (250 mL). The mixture is extracted with EtOAc (2×100 mL) and thenwashed with 5% NaHCO₃ (2×50 mL) before being dried over anhydrous MgSO₄,filtered and concentrated to give the desired crude product 5b as anorange solid (8.2 g, quantitative yield). This material is used in thenext step without further purification.

Step 2:

To a well stirred ethanol solution (75 mL) of 5b (8.1 g, 34.9 mmol),SnCl₂ (20 g, 105 mmol) is added. The reaction mixture is stirred atreflux for 2.5 h. After that period, the transformation is incomplete,therefore, more SnCl₂ (2 g, 10 mmol) is added and the reaction mixtureis heated at reflux for 1 h before being cooled to RT. The mixture ispoured onto 250 g of ice and the pH adjusted to approximately 7.5 withaqueous 5% NaHCO₃. The product is extracted with EtOAc (3×100 mL) beforebeing washed with saturated brine (2×100 mL). The organic phase is driedover anhydrous MgSO₄, filtered and concentrated to dryness to give theaniline intermediate 5c as a gray solid (8.25 g, ˜100% yield; thismaterial contained some tin residues, nonetheless, it is used as suchfor the following step).

Step 3:

To a stirring, ice cold, DMF (5 mL) suspension of potassium carbonate(2.05 g, 14.8 mmol) and aniline 5c (750 mg, 3.71 mmol) under nitrogen,chloroacetyl chloride (355 μL, 4.45 mmol) is added dropwise. The mixtureis allowed to warm to RT over a period of 15 min and then heated to 60°C. for 1 h. The mixture is allowed to cool to RT, is poured into amixture of ice/water (250 mL) and is stirred for approximately 15 min.The suspension is centrifuged, and the supernatant is discarded. Thesolid material is left drying under suction overnight to giveintermediate 5d (280 mg, 31% yield).

Step 4:

To an ice cold THF (6 mL) solution of the cyclic amide 5d (280 mg, 1.16mmol) under nitrogen, a borane-THF solution (1 M in THF, 1.74 mL, 1.74mmol) is added slowly. The reaction mixture is slowly allowed to warm toRT, then is stirred at RT for 1.5 h and then gently heated to reflux for1 h to complete the conversion. The mixture is cooled in an ice bath andis carefully quenched with aqueous 1 M NaOH (4 mL) over 10 min. Thereaction mixture is partitioned between EtOAc (150 mL) and water (25mL). The organic layer is washed with aqueous 1 N NaOH (20 mL),saturated aqueous NaCl, and finally dried over anhydrous MgSO₄, filteredand concentrated to give the crude 5e as an amber oil (212 mg, 81%yield). This product is used as such for next transformation.

Step 5:

A well stirred DMF (15 mL) solution of the arylbromide 5e (0.50 g, 2.19mmol), potassium acetate (0.728 g, 7.67 mmol) andbis(pinacolato)diborane (0.83 g, 3.3 mmol) is degassed by bubbling Arthrough the solution for 20 min. PdCl₂(dppf)-DCM (320 mg, 0.44 mmol) isadded and degassing is continued for 15 min. The system is sealed(teflon screw cap vessel) under Ar and heated to 90° C. for 5 h. Thereaction mixture is allowed to cool to RT, dilute with EtOAc (150 mL),washed with brine (3×100 mL) and water (2×100 mL), dried over anhydrousMgSO₄, filtered and concentrated to dryness. The residue is purified byCombiFlash® Companion (EtOAc/hexanes) to give the desired boronate 5f(389 mg, 65% yield) as a yellowish waxy solid.

Example 6 Synthesis of Boronate Fragment 6i

Step 1:

Sodium hydride (60%, 7.78 g, 194 mmol) is added to a well stirredsuspension of 6a (12.5 g, 97.2 mmol) in THF (100 mL). After stirring thereaction mixture for 1 h, N,N-diethylcarbamoyl chloride (24.64 mL, 194mmol) is added at RT. After stirring the reaction overnight, thereaction mixture is quenched with water (100 mL), extracted with EtOAc(3×50 mL), dried over anhydrous MgSO₄, filtered and evaporated underreduced pressure to obtain 6b (33 g, 75% yield) in high purity.

Step 2:

Diisopropylamine (21.0 mL, 121 mmol) in THF (330 mL) is treated with asolution of n-BuLi (2.5 M in hexanes, 48.2 mL, 121 mmol) at 0° C. After30 min at this temperature, the solution is cooled to −78° C. andcarbamate 6b (33.29 g, 109.7 mmol, 75% pure) is added. The reaction isstirred at this temperature for 30 min and then iodine (33.4 g, 132mmol) is added. The solution is stirred for 30 min at 0° C. and is thenwarmed to RT. After 2 h, the reaction mixture is quenched with water(250 mL) and the volatile organic solvents are removed under reducedpressure. The aqueous phase is then extracted with EtOAc (3×100 mL),washed with 1 N HCl (1×200 mL), dry MgSO₄, filtered and evaporated underreduced pressure to obtain 6c (18.6 g, 39% yield).

Step 3:

The iodo 6c (10 g, 28 mmol), propargyl alcohol (3.3 mL, 56 mmol),Pd(PPh₃)₄ (3.27 g, 2.83 mmol) and copper iodide (1.08 g, 5.66 mmol) arecombined in diisopropylamine (39 mL, 39 mmol) in a sealable tube underAr and heated at 100° C. After 1 h, the reaction mixture is cooled to RTand poured into EtOAc (100 mL) and this mixture is extracted with 10%HCl (2×100 mL). The organic layer is dried over MgSO₄ and concentratedto dryness. The crude product is purified by CombiFlash® Companion toobtain 6d (3.65 g, 46% yield).

Step 4:

6d (3.63 g, 12.9 mmol) is dissolved in EtOAc (81 mL) and treated withRh—Al₂O₃ (5% w/w, 3.45 g, 1.68 mmol). The flask is evacuated and chargedwith 1 atmosphere of H₂ (balloon) and the reaction is stirred overnightat RT. The reaction mixture is filtered through Celite® (EtOAc wash) andthe filtrate is concentrated under reduced pressure. The residue is thenpurified by CombiFlash® Companion to obtain 6e (3.7 g, 71% yield).

Step 5:

Solid NaOH (920 mg, 23 mmol) is added to a solution of 6e (2.63 g, 9.20mmoL) in EtOH (93 mL) and the mixture is heated to reflux and is stirredovernight. The mixture is then cooled to RT and the organic solventremoved under reduced pressure. Water is added (100 mL) and the mixtureextracted with Et₂O (3×100 mL), dried over MgSO₄, filtered andevaporated under reduced pressure to obtain phenol 6f (869 mg, 51%yield).

Step 6:

Diethyl azodicarboxylate (953 μL, 6.05 mmol) is added dropwise to asolution of phenol 6f (869 mg, 4.66 mmol) and PPh₃ (1.59 g, 6.05 mmol)in THF (65 mL) and the reaction is stirred at RT. After 4 h, thereaction mixture is evaporated under reduced pressure. The residue isthen purified by CombiFlash® Companion to obtain the chromanintermediate 6g (387 mg, 49% yield).

Step 7:

Iodine (583 mg, 2.29 mmol) is added to a solution of chroman 6g (387 mg,2.29 mmol) and AgNO₃ (429 mg, 2.52 mmol) in MeOH (23 mL). After 20 min,a 0.5 M solution of sodium thiosulfate (10 mL) is added and the aqueousphase extracted with EtOAc (3×25 mL). The combined organic phases arewashed with brine, then dried (MgSO₄), filtered and evaporated to obtainaryl iodide 6h (647 mg, 96% yield).

Step 8:

A solution of iodo intermediate 6h (647 mg, 2.20 mmol),bis(pinocolato)diborane (0.725 g, 2.86 mmol) and potassium acetate(0.626 g, 6.59 mmol) in DMF (17 mL) is degassed with Ar for 10 min.PdCl₂(dppf)-DCM complex (179 mg, 0.22 mmol) is then added and themixture is degassed with Ar for approximately another 5 min. Thereaction is then heated to 95° C. in a sealable tube and is stirredovernight. The reaction is cooled to RT and EtOAc (100 mL) is added. Thesolution is washed with brine (3×150 mL), water (1×150 mL), dried overMgSO₄, filtered and solvent removed under reduced pressure. The residueis purified by CombiFlash® Companion to afford boronate ester 6i (260mg, 40% yield).

Example 7 Synthesis of Boronate Fragment 7d

Step 1:

A solution of phenol 7a (0.91 g, 5.74 mmol) in dry DMF (1 mL) is addeddropwise to a slurry of NaH (60% in oil, 0.60 g, 15 mmol) in dry DMF (1mL) cooled to 10-15° C. (cold water bath) and the mixture is stirred for20 min. This results in a thick, frothy white mixture. A solution of3-bromopropionic acid (1.1 g, 6.9 mmol) in dry DMF (0.5 mL) is thenadded dropwise and the reaction stirred at RT overnight. After 16 h,methanol (1.2 mL) is added to help break up the thick, pasty reactionmixture which is then added to diluted HCl (12 mL, 1 N HCl in 100 mLwater) and extracted with EtOAc (80 mL; the pH of the aqueous phase isadjusted to pH<3). The organic layer is dried over anhydrous Na₂SO₄ andevaporated to give 7b as a white solid material, contaminated with someunreacted SM (1.29 g of crude material). This material is used in thenext step without purification.

Step 2:

The crude compound 7b (1.53 g, 6.63 mmol) is combined withpolyphosphoric acid (approximately 7 g) and heated to 75° C. to give acherry red colored solution. During the reaction time, the reactionmixture becomes viscous and stirring becomes difficult. After 4 h, thereaction is cooled; ice and water are slowly added with rapid stirringto give a thick suspension. This mixture is transferred to a separatoryfunnel where the product is extracted with EtOAc (100 mL) and washedwith water (100 mL), saturated NaHCO₃ (2×100 mL) and brine (75 mL). Theorganic phase is dried over anhydrous MgSO₄ and evaporated to give asticky violet solid 7c which is used as such (1.29 g crude).

Step 3:

Intermediate 7c is analogous to intermediate 4b in Example 4; thoseskilled in the art would recognize that the same synthetic methodologiesused to convert 4b to the boronate 4f can be applied for the conversionof 7c to the corresponding boronate 7d.

Example 8 Synthesis of Boronate Fragment 8h

Step 1

2-Amino-m-cresol 8a (5.7 g, 46.3 mmol) is dissolved in H₂O (30 mL) and1,4-dioxan (15 mL). The mixture is heated to reflux and then HBr (48%,17 mL, 0.31 mol) is added dropwise over a period of 20 min. The refluxis maintained for an additional 15 min after the addition is complete.The reaction is cooled to 0° C., and NaNO₂ in H₂O (20 mL) is added overa period of 30 min. The stirring is continued for 15 min at 0° C., themixture is then transferred in one shot to a stirring mixture of Cu(I)Br(7.64 g, 53.2 mmol) in H₂O (20 mL) and HBr (48%, 17 mL, 0.31 mol) at 0°C. (protected from light). The reaction is stirred for 15 min at 0° C.,warmed to 60° C., stirred for an additional 15 min, cooled to RT andthen stirred overnight. The reaction mixture is then transferred to aseparatory funnel and extracted with EtOAc (3×). The organic layers arecombined, washed with brine, dried over anhydrous MgSO₄, filtered andconcentrated over silica to afford a mixture that is purified using theCombiFlash® Companion (20% EtOAc/hexanes) to afford the desired bromide8b (1.46 g, 17% yield) as a red-brown oil.

Step 2:

To a solution of the bromide 8b (1.36 g, 7.27 mmol) and (PPh₃)₂PdCl₂(766 mg, 1.09 mmol) in DMF (12 mL), 1-ethoxyvinyl-tri-n-butyltin (2.7mL, 8.0 mmol) is added. The mixture is capped and heated in a microwaveat 160° C. for 15 min. HPLC and LC-MS analysis indicate approximately70% conversion. More 1-ethoxyvinyl-tri-n-butyltin (2.7 mL; 8.0 mmol) andcatalyst (PPh₃)₂PdCl₂ (380 mg) are added and the solution is againsubjected to the same microwave conditions. The reaction is quenchedwith 6N HCl (1.5 mL) and stirred at RT for 1 h to effect hydrolysis ofthe intermediate. The mixture is poured into EtOAc (150 mL), washed withbrine (3×), dried over MgSO₄, filtered and concentrated over silica toafford the mixture that is purified using the CombiFlash® Companion (20%EtOAc/hexanes) to afford the desired ketone 8c (947 mg, 87% yield) as anorange oil.

Step 3:

The methyl ketone 8c (1.02 g, 6.8 mmol) is dissolved in EtOAc (15 mL)and CHCl₃ (15 mL) before being treated with Cu(II)Br₂ (3.03 g, 13.6mmol). The mixture is heated to reflux for 16 h. The mixture is cooledto RT, the product filtered and washed with EtOAc (1×). The solution isconcentrated over silica to afford the mixture that is purified usingthe CombiFlash® Companion (10% EtOAc/hexanes) to afford theα-bromoketone 8d (710 mg, 46% yield) as an orange oil. This material isused as is in the next step without purification.

Step 4:

To a solution of the bromoketone 8d (710 mg, 3.1 mmol) in anhydrous DMF(12 mL), KF (400 mg, 6.95 mmol) is added. The reaction is stirred at RTfor 16 h. The mixture is taken up in EtOAc (150 mL), washed with brine(3×), dried over anhydrous MgSO₄, filtered and concentrated over silicato afford the mixture that is purified using the CombiFlash® Companion(20% EtOAc/hexanes) to afford the cyclic ketone 8e (280 mg, 61% yield)as a pale orange solid.

Step 5:

Zn dust pre-activation procedure: Zinc dust (20 g, 350 mesh) is placedin a round bottom flask and 1 N HCl (50 mL) is added. This suspension issonicated for 1 min before decanting off the liquid. This procedure isrepeated for a second time after which the solid is washed with EtOH(2×), Et₂O (2×) and dried under high vacuum. To a solution of the ketone8e (280 mg, 1.89 mmol) in AcOH (10 mL) pre-activated Zn dust (1.24 g,18.9 mmol) is added. The reaction mixture is then heated to 75° C. for 2h. The reaction mixture is filtered (with EtOAc washing of the solids).The solvent is evaporated over silica and the mixture is directlypurified using the CombiFlash® Companion (10% EtOAc/hexanes) to affordthe desired dihyrobenzofuran 8f (174 mg, 69% yield) as a colorless oil.

Step 6:

To a solution of the dihydrobenzofuran 8f (240 mg, 1.8 mmol) in MeOH (5mL), AgNO₃ (304 mg, 1.79 mmol) is added followed by iodine (453 mg, 1.79mmol). The yellow mixture is stirred at RT for 1 h. To the reactionmixture is added a solution of 10% Na₂S₂O₃ and the mixture is stirredfor 15 min at RT. The mixture is diluted with EtOAc (100 mL), and theorganic layer is washed with brine (3×) and 10% Na₂S₂O₃ (2×). Theorganic phase is dried over anhydrous MgSO₄, filtered and concentratedover silica to give a mixture. This mixture is purified using theCombiFlash® Companion (10% EtOAc/hexanes) to afford the iodo derivative8g (400 mg, 86% yield) as a white amorphous solid.

Step 7:

A mixture of the iodo derivative 8g (400 mg, 1.54 mmol),bis(pinocolato)diborane (585 mg, 2.31 mmol), potassium acetate (511 mg,5.4 mmol) in DMF (20 mL) is degassed (Ar balloon and sonication for 5min); then the catalyst (PdCl₂dppf, 188 mg, 0.23 mmol) is added withadditional degassing (Ar balloon and sonication for 2 min). The mixtureis then heated to approximately 95° C. for 4 h. The mixture is cooled,EtOAc (200 mL) is added, washed with brine (3×), water (2×), dried overanhydrous MgSO₄, filtered and solvent evaporation over silica affordsthe mixture that is purified using the CombiFlash® Companion (10%EtOAc/hexanes) to afford the desired boronate 8h (315 mg, 79% yield) asa yellow oil.

Example 9 Synthesis of Boronate Fragment 9b

Anhydrous DMF (60 mL) is added to a flask charged with bromide 9a (5.00g, 22.2 mmol), bis-(pinacolato)diborane (8.48 g, 33.4 mmol) andpotassium acetate (6.35 g, 66.8 mmol) and the resulting suspension isdeoxygenated by bubbling a stream of N₂ gas through the mixture for 45min. 1,1′-bis(diphenylphosphino)ferrocene (2.73 g, 3.34 mmol) is thenadded and the mixture is deoxygenated for approximately a further 5 minand is then heated to 95° C. After 16 h, the dark reaction mixture iscooled, extracted with EtOAc (500 mL and 300 mL) and washed with 1:1water/brine (600 mL) and brine (600 mL). The combined extracts are driedover anhydrous MgSO₄, filtered and evaporated to a black syrup which ispurified by flash column chromatography (EtOAc/hexane) to afford theboronate 9b as white solid contaminated with <25% of the diboron reagent(4.24 g, 62% yield).

Example 10 Synthesis of Boronate Fragment 10g

Step 1:

2-Chloro-6-fluoronitrobenzene 10a (6.62 g, 37.7 mmol) and LiOHmonohydrate (6.33 g, 151 mmol) are dissolved in THF (45 mL) and water(65 mL) and an aqueous solution of H₂O₂ (30%, 8.60 mL, 80.0 mmol) added.The resulting turbid solution is sealed and is heated to 60° C. withrapid stirring. After 3 days, the dark orange mixture is cooled and isadded to half-saturated aqueous sodium thiosulfate (200 mL) and shakenvigorously in a separatory funnel. The mixture is then acidified to pH<3with 1 N HCl, extracted with EtOAc (500 mL) and washed with brine (400mL). The combined extracts are dried over magnesium sulfate, filteredand evaporated to a deep yellow oil (aminophenol 10b) containing somesolid particles (residual starting material) which is used as such (6.37g, 97% yield).

Step 2:

The crude aminophenol 10b (6.37 g, 36.7 mmol) is dissolved in THF (100mL) and tin powder (17.4 g, 147 mmol) is added followed by 1 N HCl (220mL, 220 mmol). The resulting mixture is stirred vigorously at RT. After16 h, the reaction is cooled to 0° C., the acid neutralized with 10 NNaOH (22 mL) and the resulting milky suspension stirred vigorously for15 min. The mixture is then filtered through a pad of Celite® and thesolids washed thoroughly with EtOAc (4×200 mL). The filtrate istransferred to a separatory funnel and the aqueous phase acidified with1 N HCl (4 mL), diluted with brine (400 mL) and the organic phase washedwith brine (400 mL). The extract is then dried over sodium sulfate,filtered and evaporated to afford aminophenol 10c as a waxy, pale brownsolid (2.91 g, 55% yield).

Step 3:

Chloroacetyl chloride (1.94 mL, 24.3 mmol) is added to an ice-coldmixture of aminophenol 10c (2.91 g, 20.3 mmol) and potassium carbonate(8.40 g, 60.8 mmol) in anhydrous DMF (200 mL) under a N₂ atmosphere.After 5 min, the reaction is allowed to warm to RT and, after a further45 min, is heated to 50° C. After 15 h, the reaction is cooled andextracted with EtOAc (600 mL) and washed with water/brine (1 L),half-saturated sodium bicarbonate (1 L) and brine (600 mL). The organicphase is then dried over MgSO₄, filtered and evaporated to afford lactam10d as a fibrous, pale-olive solid (3.15 g, 85% yield).

Step 4:

Bromine (1.8 mL; 35 mmol) is slowly added dropwise to a stirred solutionof lactam 10d (3.15 g; 17.1 mmol) in anhydrous DCM (40 mL) at RT. After3 h, the resulting suspension is slowly added to saturated aqueoussodium thiosulfate (200 mL) and extracted with DCM (4×100 mL). Thecombined extracts are then washed with brine (200 mL), dried overmagnesium sulfate, filtered and evaporated to afford the bromide 10e asa pale beige powder (4.00 g, 89% yield).

Step 5:

A solution of borane in THF (1.0 M, 18.5 mL, 18.5 mmol) is addeddropwise to an ice-cold solution of lactam 10e (4.00 g, 15.2 mmol) inanhydrous THF (75 mL), and the reaction is allowed to warm to RT. After30 min, the solution is heated to gentle reflux under a N₂ atmosphere.After 2 h, the reaction is cooled to 0° C. and carefully quenched with 1N NaOH (19 mL) and stirred for 15 min. The mixture is then diluted withwater (30 mL) and the THF is evaporated. The aqueous residue is thenextracted with EtOAc (400 mL+50 mL) and washed with water/brine (200mL), 0.5 N NaOH (200 mL) and brine (100 mL). The combined extracts aredried over magnesium sulfate, filtered and evaporated to afford themorpholine derivative 10f as a yellow syrup (3.90 g, quantitativeyield).

Step 6:

Anhydrous DMF (30 mL) is added to a flask charged with aryl bromide 10f(1.84 g, 7.42 mmol), bis(pinacolato)diborane (2.83 g, 11.1 mmol) andpotassium acetate (2.47 g, 26.0 mmol) and the resulting suspension isthen deoxygenated by bubbling a stream of N₂ gas through the mixture for15 min. 1,1′-bis(diphenylphosphino)ferrocene (909 mg, 1.11 mmol) is thenadded and the mixture is deoxygenated for a further 5 min and thenheated to 95° C. After 16 h, the dark reaction mixture is cooled,diluted with EtOAc (300 mL) and washed with 1:1 water/brine (500 mL) andbrine (200 mL). The extract is then dried over MgSO₄, filtered andevaporated to a brown syrup which is chromatographed over silica gel(EtOAc/hexanes) to afford the boronate 10g as a white solid contaminatedwith 0.8 eq of the diboron reagent (1.52 g, 69% yield).

Example 11 Synthesis of Boronate Fragment 11d

Step 1:

Commercially available chromanone 11a (9.78 g, 66.0 mmol) dissolved inAcOH (20 mL) is added to a suspension of zinc dust (108 g, 1.65 mol) inAcOH (150 mL). The mixture is heated to 100° C. and is stirredmechanically overnight. The mixture is then filtered through Celite®(washed with EtOAc, 100 mL), diluted with PhMe (300 mL) and the solutionis evaporated to give chroman intermediate 11b (8.45 g, 95% yield).

Step 2:

AgNO₃ (12.0 g, 70.6 mmol) and I₂ (15.8 g, 62.3 mmol) are addedsequentially to a solution of 11b (8.45 g, 63.0 mmol) dissolved in MeOH(225 mL). The reaction is allowed to stir for 1 h, filtered on Celite®and the filtrate concentrated under reduced pressure. The crude mixtureis diluted with EtOAc (250 mL) and washed with saturated sodiumthiosulfate (250 mL). The organic layer is washed with water (200 mL)and then dried over Na₂SO₄, filtered and concentrated. The crude mixtureis further purified by CombiFlash® Companion to give 6-iodochroman 11c(12.1 g, 74% yield).

Step 3:

A solution of the 6-iodochroman 11c (1.0 g, 3.85 mmol),bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.10g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for 5 min followed bythe addition of the PdCl₂dppf-DCM complex (314 mg, 0.38 mmol). Thereaction mixture is then degassed for an additional 5 min before beingheated to 95° C. for 5 h. The reaction is then cooled to RT. The crudereaction mixture is diluted with water and the product is extracted withEtOAc (3×100 mL). The combined organics are washed with water (100 mL)and brine (100 mL). The organic phase is then dried over MgSO₄ andfiltered and concentrated. The crude mixture is further purified byCombiFlash® Companion using a gradient of EtOAc/hexanes to afford theborane fragment 11d (840 mg, 84% yield).

Example 12 Synthesis of Boronate Fragment 12g

Step 1:

The phenol 12a (6.75 g, 47.3 mmol) is dissolved in DMF (270 mL) and istreated with allyl bromide (6.55 mL, 75.7 mmol). To this solution, NaH(60%, 4 g, 99.4 mmol) is added portionwise and stirring is continuedovernight. The reaction mixture is diluted with EtOAc (500 mL) andwashed with H₂O (3×500 mL). The organic layer is dried over MgSO₄,filtered and concentrated to dryness to obtain the desired product 12b,which is used as such in the next step.

Step 2:

The ether 12b (9.67 g) is placed in a microwave vial neat with a stirbar and is heated to 240° C. for 20 min at which point the Claisenrearrangement reaction is complete. The crude product 12c (9.3 g) isused in the following step without further purification.

Step 3:

To a solution of the allyl intermediate 12c (9.3 g, 45.8 mmol) inanhydrous THF (300 mL) at 0° C., borane (1 M in THF, 96 mL, 96 mmol, 2.1eq) is added. The solution is allowed to warm to RT and then is stirredfor 2.5 h. The solution is then cooled to 0° C. and treated with 10 NNaOH dropwise, followed by slow addition of 30% H₂O₂ (104 ml, 916 mmol).The resulting mixture is allowed to warm to RT and then is stirred at RTfor 1 h. The reaction mixture is diluted with HCl (10%, 100 mL) andextracted with EtOAc (3×200 mL). The combined organic phases are driedover MgSO₄ and concentrated. The crude product is purified byCombiFlash® Companion to give 12d (7.1 g, 77% yield).

Step 4:

To a solution of the diol 12d (7.1 g, 35.3 mmol) in THF (500 mL), PPh₃(12 g, 45.9 mmol), followed by DEAD (7.2 mL, 45.9 mmol) are added. Thesolution is stirred at RT for 4 h. The reaction mixture is evaporatedunder reduced pressure and purified by CombiFlash® Companion to obtainthe desired product 12e (5.26 g, 82% yield).

Step 5:

The chroman derivative 12e (5.26 g, 28.8 mmol) is dissolved in AcOH (70mL) and is then treated with Br₂ in AcOH (40 mL). The reaction isstirred at RT for 15 min, then diluted with toluene and concentrated todryness. The residue is taken up in EtOAc (25 mL) and washed withsaturated Na₂S₂O₃ (25 mL) and saturated NaHCO₃ (25 mL). The organiclayer is dried over MgSO₄, concentrated and purified by CombiFlash®Companion to obtain the desired product 12f (2.7 g, 36% yield).

Step 6:

The bromide 12f (2.71 g, 10.4 mmol) is dissolved in DMF (120 mL) andtreated with bispinocolatoborane (4 g, 15.5 mmol) and potassium acetate(3.45 g, 36.3 mmol). The mixture is degassed (using an Ar balloon)before the introduction of the catalyst (PdCl₂dppf, 845 mg, 1.04 mmol).The mixture is then degassed again (using an Ar balloon) and heated to95° C. for 16 h. The mixture is cooled to RT, diluted with H₂O (300 mL)and extracted with EtOAc (2×300 mL). The combined organic layers arewashed with water (3×300 mL) dried over MgSO₄, filtered andconcentrated. The product is then purified by CombiFlash® Companion. Thesemi-purified product is then triturated with hexanes (3×50 mL) in orderto remove the excess disborane and obtain clean compound 12g (1.74 g,54% yield).

Example 13 Synthesis of Boronate Fragment 13a

Step 1:

Palladium on activated charcoal (10% Pd by weight, 0.63 mg, 0.59 mmol)is added to a solution of aryl chloride 12g (0.91 g, 2.95 mmol) andammonium formate (1.92 g, 30.4 mmol) dissolved in MeOH and the mixtureis heated to reflux. After 15 min, the reaction is cooled to RT andfiltered through Celite® (MeOH rinse). The filtrate is evaporated todryness and the residue partitioned between water and EtOAc (10 mLeach). The organic layer is dried over anhydrous MgSO₄ and concentratedto obtain boronic ester 13a (0.78 g, 97% yield).

Example 14 Synthesis of Boronate Fragment 14g

Step 1:

Allyl bromide (9.3 mL, 110 mmol) followed by potassium carbonate (20 g,150 mmol) are added to a solution of 14a (10 g, 73 mmol) dissolved inDMF (110 mL). The reaction is allowed to stir under Ar at RT overnight.The reaction is diluted with water (400 mL) and extracted with EtOAc(400 mL). The organic layer is washed with water (2×400 mL), dried overNa₂SO₄ and concentrated. The product is then purified by CombiFlash®Companion in two batches to provide allyl ether 14b (12 g, 92% yield).

Step 2:

A solution of n-BuLi in hexanes (2.5 M, 6.4 mL, 16 mmol) is addeddropwise to a precooled (−78° C.) suspension ofmethyltriphenylphosphonium bromide (6.6 g, 19 mmol) in THF (90 mL). Theresulting bright yellow mixture is stirred for 5 min at −78° C., warmedto RT over approximately 5 min and then recooled to −78° C. Aldehyde 14b(2.4 g, 14 mmol) dissolved in THF (10 mL) is added dropwise and thereaction is allowed to proceed for 10 min at −78° C. before beingallowed to warm to RT and stir overnight. The reaction is quenched withbrine (100 mL), diluted with water (100 mL) and extracted with EtOAc(100 mL). The organic layer is then washed with water (2×100 mL), driedover Na₂SO₄ and concentrated. The crude yellow liquid is then taken upin EtOAc (1 mL) and diluted with hexanes (20 mL), after which Ph₃POprecipitates as a white solid. The solid is removed by filtration,washed with 1:9 EtOAc:hexanes (50 mL) and the filtrates are evaporatedto dryness. The product is purified by CombiFlash® Companion to givediene 14c (1.3 g, 54% yield).

Step 3:

Grubb's second generation catalyst (50 mg, 0.075 mmol) is added to adegassed solution of diene 14c (1.3 g, 7.5 mmol). After stirring underAr for 2.5 h, the reaction is concentrated onto SiO₂ (about 2 g) and theproduct purified by CombiFlash® Companion to give benzopyran 14d (940mg, 86% yield) as a clear oil.

Step 4:

Solid Pd—C (10% w/w, 680 mg, 0.64 mmol) is added to a solution ofbenzopyran 14d (940 mg, 6.4 mmol) in EtOH (8.5 mL) and the flask isevacuated and backfilled with H₂ gas (balloon). After stirring thereaction at RT for 2.5 h, the mixture is filtered through Celite® (EtOAcwashing) and then the filtrate is concentrated to dryness. The productis purified by CombiFlash® Companion to provide chroman 14e (800 mg, 84%yield).

Step 5:

Neat Br₂ (275 μL, 5.4 mmol) is added dropwise to a solution of chroman14e (800 mg, 5.4 mmol) dissolved in AcOH (25 mL). The reaction is thendiluted with water (50 mL) and EtOAc (50 mL). The organic layer iswashed with water (2×50 mL) and saturated NaHCO₃ (2×50 mL). The organiclayer is dried over Na₂SO₄ and concentrated to dryness. The product ispurified by CombiFlash® Companion to give bromide 14f as a mixture withthe dibromide (1.3 g, 68% by mass 14f, 51% yield).

Step 6:

A solution of the bromide 14f (950 mg, 2.8 mmol),bis[pinocolato]diborane (840 mg, 3.3 mmol) and potassium acetate (920 g,9.6 mmol) in DMF (30 mL) is degassed with Ar for 5 min followed by theaddition of the PdCl₂dppf-DCM complex (290 mg, 0.36 mmol). The reactionmixture is then degassed for an additional 5 min before being heated to95° C. for 3 h. The reaction is then cooled to RT. The crude reactionmixture is diluted with water and the product is extracted 3 times withEtOAc (3×20 mL). The combined organics are washed with water (2×20 mL).The organic phase is then dried over Na₂SO₄, filtered and concentrated.The crude mixture is further purified by CombiFlash® Companion to affordboronic ester 14g (403 mg, 53% yield) as a pale yellow solid.

Example 15 Synthesis of Boronate Fragment 15l

Step 1:

An ethereal solution of diazomethane (0.7 M, 100 mL) is added to asolution of 15a (5.0 g, 30 mmol) in ether (20 mL). After consumption ofthe SM (TLC monitoring), the reaction is concentrated onto SiO₂ (about10 g) and the product purified by CombiFlash® Companion to yield ester15b (5.2 g, 95% yield).

Step 2:

A solution of NaNO₂ (2.1 g, 30 mmol) in water (10 mL) is slowly added toa solution of aniline 15b (5.0 g, 28 mmol) dissolved in AcOH (50 mL) and2 M HCl (75 mL) at 0° C. The resulting mixture is stirred at thistemperature for 1 h. Solid CuCl (8.4 g, 85 mmol) is added portionwise(over 2 min). The reaction is allowed to come to RT, is stirred for 30min and then is warmed to 60° C. for 40 min. The mixture is poured intowater (200 mL) and extracted with EtOAc (2×200 mL). The organic layer isdried with MgSO₄, filtered and evaporated to dryness. The product ispurified by CombiFlash® Companion to afford aryl chloride 15c (3.8 g,68% yield).

Step 3:

A solution of DIBAL in DCM (1 M, 42 mL, 42 mmol) is added dropwise overa period of 25 min to a precooled (−78° C.) solution of ester 15c (3.8g, 19 mmol) in dry CH₂Cl₂ (100 mL). The reaction is allowed to stir for2 h at −78° C. The reaction is quenched at −78° C. by the dropwiseaddition of 1 N HCl (8 mL). The reaction is allowed to warm to RT andthe organic phase washed with a 5% solution of Rochelle's salt (100 mL),dried over MgSO₄, filtered and concentrated under reduced pressure togive crude benzyl alcohol 15d (3.2 g, 99% yield), which is used in thenext step without any further purification.

Step 4:

Solid Dess Martin reagent (8.7 g, 20 mmol) is added to a precooled (0°C.) solution of alcohol 15d in dry CH₂Cl₂ (100 mL). The reaction isallowed to stir for 2 h while slowly warming to RT. At this time,another 0.5 g of Dess Martin Periodinane is added and the reactioncontinues for another 1 h. A 1:1 mixture of saturated NaHCO₃ and 0.5 MNa₂S₂O₃ (100 mL) is added and this mixture is stirred vigorously untilthe phases become clear (approximately 30 min). The organic phase isseparated and the aqueous phase is extracted with DCM (100 mL) andwashed with saturated NaHCO₃ (100 mL). The combined organic phases arethen dried over MgSO₄ and evaporated. The product is purified byCombiFlash® Companion to give aldehyde 15e (2.9 g, 90% yield).

Step 5:

A solution of methyl ether 15e (720 mg, 4.2 mmol) in anhydrous CH₂Cl₂(20 mL) is added slowly to a precooled (−30° C.) solution of BBr₃ (1 M,8.4 mL, 8.4 mmol). The solution is warmed to 0° C. and is stirred for 3h. The reaction is quenched carefully with methanol (1 mL) and washedwith saturated NaHCO₃ and then brine (25 mL each). The organic layer isdried over MgSO₄, filtered and concentrated and the product is purifiedby CombiFlash® Companion to give phenol 15f (530 mg, 80% yield).

Step 6:

A mixture of the aldehyde 15f (1.1 g, 7.2 mmol), acrylonitrile (2.4 mL,36 mmol) and DABCO (190 mg, 1.7 mmol) are refluxed for 5 h. The reactionmixture is cooled to RT, diluted with EtOAc (50 mL) and washed with 1 NNaOH (20 mL) and then with 1 N HCl (20 mL). The organic phase is driedover MgSO₄ and concentrated to dryness. The product is purified byCombiFlash® Companion to afford the nitrile 15g (650 mg, 47% yield).

Step 7:

A mixture of nitrile 15g (650 mg, 3.4 mmol), 10% NaOH (10 mL, 25 mmol)and EtOH (95%, 0.5 mL) is heated to reflux for 5 days. The reaction isthen cooled to RT and 1 N HCl is then added until pH 4. The precipitateis then collected by filtration, washed with water and dried in vacuo togive acid 15h (740 mg, >99% yield).

Step 8:

Triethylamine (0.56 mL, 4.0 mmol) and diphenylphosphoryl azide (0.75 mL,3.5 mmol) are added successively to a solution of acid 15h (714 mg, 3.4mmol) in dry toluene (40 mL). This mixture is heated to 85° C. for 2 hand then cooled to RT and treated with 6 N HCl (6 mL). The mixture isbrought to reflux and is stirred at this temperature for 2 h. Thereaction is then cooled to RT, diluted with EtOAc (100 mL) and washedwith saturated NaHCO₃ (2×100 mL), water (2×100 mL) and brine (100 mL).The organic layer is dried over MgSO₄, filtered and evaporated todryness. The product is then purified by CombiFlash® Companion to giveketone 15i (269 mg, 44% yield).

Step 9:

Deoxofluor® (0.54 mL, 2.9 mmol) is added to a solution of ketone 15i(270 mg, 1.5 mmol) in CH₂Cl₂ (0.6 mL) and EtOH (17 μL) in a sealed tube.The sealed tube is heated to 40° C. for 24 h. The tube is then unsealed,cooled to 0° C. and the reaction quenched by the slow (Exothermic)addition of saturated NaHCO₃ (1 mL). The crude reaction mixture isdiluted with water (20 mL) and extracted with DCM (3×20 mL). Thecombined organics are washed with water (20 mL) and the organic phase isdried over MgSO₄, filtered and concentrated. The product is purified byCombiFlash® Companion to provide difluorochroman 15j (225 mg, 71%yield).

Step 10:

Solid silver nitrate (187 mg, 1.1 mmol) and iodine (279 mg, 1.1 mmol)are added successively to a solution of difluorochroman 15j (225 mg, 1.1mmol) dissolved in MeOH (7.8 mL). The reaction is stirred at RT for 90min and then filtered through a pad of Celite®. The filtrate is treatedwith a drop of 0.5 N Na₂S₂O₃ (orange color dissipated) then concentratedunder reduced pressure. The residue is partitioned between H₂O, 0.5NNa₂S₂O₃ and EtOAc (20 mL each). The water layer is extracted with EtOAc(3×20 mL) and the combined organics are washed with brine (20 mL), driedover MgSO₄, filtered and concentrated. The product is purified byCombiFlash® Companion to give aryl iodide 15k (158 mg, 44% yield).

Step 11:

A solution of the aryl iodide 15k (150 mg, 0.45 mmol),bis[pinocolato]diborane (150 mg, 0.59 mmol) and potassium acetate (130mg, 1.4 mmol) in DMF (5 mL) is degassed with Ar for 5 min followed bythe addition of the PdCl₂dppf-DCM complex (44 mg, 0.054 mmol). Thereaction mixture is then degassed for an additional 5 min before beingheated to 85° C. for 9 h. The reaction is then cooled to RT. The crudereaction mixture is diluted with water and the product is extracted withEtOAc (3×10 mL). The combined organics are washed with water (10 mL) andbrine (10 mL). The organic phase is then dried over MgSO₄ and filteredand concentrated. The crude mixture is further purified by CombiFlash®Companion to afford boronic ester 15l (123 mg, 70% pure by NMR, 57%yield).

Example 16 Synthesis of Boronate Fragment 16c

Step 1:

Solid NaBH₄ (342 mg, 9.0 mmol) is added to a solution of ketone 4b (1.5g, 7.5 mmol) dissolved in MeOH (10 mL) and THF (25 mL) at 0° C. is thenadded. The reaction is warmed to RT and is allowed to stir for 1 h. Thereaction is quenched with aqueous HCl (1 N, 5 mL), the MeOH is removedby concentration and the product extracted with EtOAc (2×50 mL). Theorganic layer is washed with brine (50 mL), dried over Na₂SO₄, filteredand concentrated to afford alcohol 16a (1.52 g>99% yield). This materialis used as is in the next step.

Step 2:

TFA (2.9 mL) is added dropwise to a solution of crude alcohol 16a (1.5g; 7.47 mmol) in DCM (28 mL) at 0° C. The solution is stirred for 30min, then concentrated to dryness. The residue is taken up in EtOAc,washed with NaHCO₃ (saturated), brine, dried over Na₂SO₄, filtered andconcentrated to a pale yellow gum. The product is purified byCombiFlash® Companion to afford benzofuran 16b (0.30 g, 22% yield) as awhite solid.

Step 3:

Compound 16c is prepared from 16b following a synthetic sequenceidentical to steps 3 to 5 of Example 4.

Example 17 Synthesis of Boronate Fragment 17g

Step 1:

Zn dust (7.89 g, 121 mmol) is added to a solution of 17a (5.0 g, 24mmol) in AcOH (100 mL). The reaction mixture is then heated to 100° C.and is stirred overnight. The reaction is cooled to RT and the mixtureis filtered (EtOAc washing), the solvent is evaporated and the residuepurified by CombiFlash® Companion (30% EtOAc/hexanes) to afford aniline17b (3.06 g, 72% yield) as a yellow solid.

Step 2:

A solution of NaNO₂ (640 mg, 9.3 mmol) in water (3 mL) is slowly addedto a solution of aniline 17b (1.5 g, 8.5 mmol) dissolved in AcOH (12 mL)and 2 M HCl (25 mL) at 0° C. The resulting mixture is stirred at thistemperature for 1 h. Solid CuCl (2.6 g, 26 mmol) is added portionwise(over 2 min) and the reaction is allowed to come to RT, is then stirredfor 30 min and then is warmed to 60° C. for 40 min. The mixture ispoured into water (100 mL) and extracted with EtOAc (2×100 mL). Theorganic layer is dried with MgSO₄, filtered and evaporated to dryness.The product is purified by CombiFlash® Companion (40% EtOAc/hexanes) toafford aryl chloride 17c (1.11 g, 99% yield) as a pale yellow solid.

Step 3:

Solid pre-activated Zn dust is added to a solution of ketone 17c inAcOH. The reaction mixture is then heated to 100° C. and stirred at thattemperature for 4 h. The reaction mixture is filtered (EtOAc washing),the filtrate is evaporated to dryness and the product purified byCombiFlash® Companion (10% EtOAc/hexanes) to afford indane 17d (902 mg,88% yield) as a white crystalline solid.

Step 4:

A solution of BBr₃ in DCM (1 M, 9.9 mL, 9.9 mmol) is added dropwise to aprecooled (−78° C.) solution of methyl ether 17d (902 mg, 4.9 mmol)dissolved in DCM (20 mL). The reaction solution is stirred at thistemperature for 10 min and allowed to warm to RT. After stirring for 1.5h, water (50 mL) is added (Exothermic) and the mixture is extracted withDCM (3×50 mL). The combined organic layers are dried over MgSO₄,filtered and evaporated to dryness. The product is purified byCombiFlash® Companion to afford phenol 17e (700 mg, 84% yield) as anoff-white solid.

Step 5:

Tf₂O (1.05 mL, 12 mmol) is added to a precooled (0° C.) solution ofphenol 17e (700 mg, 4.1 mmol) and Et₃N (1.7 mL, 12 mmol) in DCM (20 mL).The resulting dark solution is allowed to warm to RT. After 25 min, thereaction is quenched with saturated NaHCO₃ (10 mL), diluted with DCM,and the organic layer washed with water, brine, dried over MgSO₄ andevaporated to dryness. The product is purified by CombiFlash® Companion(10% EtOAc/hexanes) to afford triflate 17f (1.21 g, 97% yield) as ayellow oil.

Step 6:

A solution of triflate 17f (1.2 g, 4.0 mmol), bis[pinocolato]diborane(1.5 g, 6.0 mmol) and potassium acetate (1.3 g, 14 mmol) in DMF (20 mL)is degassed with Ar for 5 min followed by the addition of thePdCl₂dppf-DCM complex (490 mg, 0.60 mmol). The reaction mixture is thendegassed for an additional 5 min before being heated to 95° C. for 5 h.The reaction is then cooled to RT. The crude reaction mixture is dilutedwith water and the product is extracted with EtOAc (3×100 mL). Thecombined organics are washed with water (100 mL) and brine (100 mL). Theorganic phase is then dried over MgSO₄ and filtered and concentrated.The crude mixture is further purified by CombiFlash® Companion (10%EtOAc/hexanes) to afford boronic ester 17g (593 mg, 53% yield) as a paleyellow solid.

Example 18 Synthesis of Boronate Fragment 18d

Step 1:

Neat Tf₂O (0.83 mL, 4.9 mmol) is added dropwise to a cooled (0° C.)solution of phenol 18a (0.50 g, 3.1 mmol) and pyridine (1.3 mL, 17 mmol)in DCM (15 mL). The reaction is allowed to warm to RT and stirovernight. The reaction is quenched by the addition of a 10% citric acidsolution (50 mL) and the mixture is extracted with DCM (3×50 mL). Thecombined organics are washed with water (50 mL), dried over MgSO₄,filtered and concentrated. The product is purified by CombiFlash®Companion to give triflate 18b (500 mg, 94% yield).

Step 2:

Deoxyfluor® (0.83 mL, 4.2 mmol) followed by EtOH (10 uL, 0.2 mmol) areadded to neat triflate 18b (500 mg, 1.7 mmol) in a sealable tube. Thetube is sealed and the reaction is heated in an oil bath at 85° C. andis stirred overnight. The reaction is then cooled to 0° C. and quenchedby the slow addition of NaHCO₃ (100 μL, Exothermic). The mixture isdiluted with water (50 mL) and extracted with DCM (3×50 mL). Thecombined organic layers are washed with water (50 mL) and brine (50 mL).The organic phase is then dried over MgSO₄, filtered and concentrated.The crude product is purified by CombiFlash® Companion to provide thedifluorotetrahydronaphtyl triflate 18c (175 mg, 33% yield).

Step 3:

Step three is performed exactly as in step 6 of Example 17 to provideboronic ester 18d.

Example 19 Synthesis of Boronate Fragment 19d

Step 1;

Solid N-chlorosuccinimide (2.2 g, 16 mmol) is added in portions over 5min to a solution of naphthylamine 19a (2.3 g, 16 mmol) dissolved inCCl₄ (150 mL). The reaction is then heated to 50° C. and is stirred for40 min. The reaction is then cooled to RT, solids are removed byfiltration and the filtrate is washed with water (100 mL), dried overMgSO₄ and evaporated to dryness to provide chloroaniline 19b (2.8 g, 96%yield).

Step 2:

A solution of NaNO₂ (1.2 g, 17 mmol) in water (5 mL) is slowly added toa precooled (0° C.) suspension of aniline 19b (2.8 g, 15 mmol) in 12 NHCl (7 mL) and ice (9.7 g), so as to maintain the temperature below 5°C. The mixture is stirred for 15 min and then is transferred to asolution of KI (8.7 g, 52 mmol) in water (30 mL) and the resultingmixture is stirred for 2 h. The mixture is extracted with Et₂O (3×100mL) and the combined organic layers washed successively with 3 N NaOH(2×50 mL), 5% NaHSO₃ (50 mL) and brine (100 mL). The organic phase isdried over MgSO₄, filtered and concentrated to dryness. The crudeproduct is purified by flash chromatography (EtOAc/hexanes) to providearyl iodide 19c (2.4 g, 54% yield).

Step 3:

Step three is carried out exactly as described in step 11 of Example 15to provide boronic ester 19d.

Example 20 Synthesis of Boronate Fragment 20d

Step 1:

Allyl bromide (2.1 mL, 25 mmol) followed by potassium carbonate (7.2 g,52 mmol) are added to a solution of 6-chlororesorcinol 20a (10 g, 69mmol) dissolved in DMF (120 mL). The reaction is stirred overnight,diluted with EtOAc (500 mL) and washed with water (3×500 mL). Theorganic layer is dried over MgSO₄ and concentrated to dryness. The crudeproduct is purified by CombiFlash® Companion to obtain allyl ether 20b(1.8 g, 40% yield).

Step 2:

Methyl iodide (1.2 mL, 20 mmol) followed by potassium carbonate (3.8 g,27 mmol) are added to a solution of phenol 20b (1.8 g, 9.8 mmol)dissolved in DMF (12 mL). The reaction is stirred for 2 h, diluted withEtOAc (50 mL) and washed with water (3×50 mL). The organic layer isdried over MgSO₄ and concentrated to dryness. The crude product ispurified by CombiFlash® Companion to obtain methyl ether 20c (1.8 g, 40%yield).

Step 3:

Step 3 is comprised of a sequence of steps identical to steps 2 through6 of Example 12, followed by step 1 of Example 13 to provide boronicester 20d.

Example 21 Synthesis of Boronate Fragment 21g

Step 1:

Solid CuBr₂ (7.9 g; 35 mmol) is added to a solution of 21a (4.0 g, 23mmol) dissolved in EtOAc (32 mL) and CHCl₃ (32 mL). The mixture isheated to reflux and is stirred for 8 h. CuBr₂ (3.9 g) is then added andthe mixture continues to stir at reflux for an additional 15 h. Themixture is cooled to RT, the solids removed by filtration (EtOAcwashing). The filtrate is concentrated to afford the crude bromoketone21b (6.3 g), which is used directly in the next step.

Step 2:

Solid KF (2.5 g, 43 mmol) is added to a solution of crude bromoketone21b (6.3 g, 23 mmol) dissolved in DMF (21 mL). The reaction is stirredat RT for 3 h and then taken up in ether (300 mL), washed with brine(3×100 mL), dried over MgSO₄, filtered and concentrated to dryness. Thecrude product is purified by CombiFlash® Companion to afford ether 21c(2.1 g, 49% yield over two steps).

Step 3:

Solid NaBH₄ (270 mg, 7.1 mmol) is added to a precooled (0° C.) solutionof ketone 21c (1.0 g, 5.9 mmol) dissolved in MeOH (20 mL). The reactionis allowed to stir for 1 h and then quenched with aqueous HCl (1 N, 1mL). The volatiles are removed in vacuo and the product extracted withEtOAc (20 mL). The organic layer is washed with brine (20 mL), dried(Na₂SO₄), filtered and concentrated to afford the crude alcohol 21d (1.0g), which is used directly in the next step.

Step 4:

Solid AgNO₃ (1.0 g, 6.1 mmol) followed by I₂(1.6 g, 6.2 mmol) are addedto a solution of alcohol 21d (1.0 g, 6.2 mmol) dissolved in MeOH (58mL). The mixture is stirred at RT for 1 h and then a solution of Na₂S₂O₄(0.5 M, 10 mL) is added and the mixture is stirred for 30 min. The MeOHis removed in vacuo and the residue taken up in EtOAc (50 mL), washedwith water (1×50 mL), brine (1×50 mL), dried (Na₂SO₄), filtered andconcentrated to afford aryl iodide 21e (1.6 g), which is used directlyin the next step.

Step 5:

Crude alcohol 21e (1.6 g, 5 mmol) is dissolved in a mixture of DCM (20mL) and TFA (2.2 mL). The reaction is stirred for 45 min and thenconcentrated to dryness. The residue is taken up in EtOAc (50 mL),washed with saturated NaHCO₃ (50 mL) and brine (50 mL). The organiclayer is dried over Na₂SO₄, filtered and concentrated to dryness. Thecrude product is purified by CombiFlash® Companion to provide benzofuran21f (978 mg, 65% yield over 3 steps).

Step 6:

Step 6 is carried out exactly as described for step 11 of Example 15 toprovide boronic ester 21g.

Example 22 Synthesis of Boronate Fragment 22d

Step 1:

Neat 3-bromo-2-methylpropene (1.7 mL, 16 mmol) is added to a suspensionof phenol 22a (3.0 g, 14 mmol) and potassium carbonate (5.6 g, 41 mmol)in DMF (35 mL). The reaction is stirred for 2 h and then quenched withwater (100 mL) and extracted with hexanes (2×100 mL). The organic phaseis washed with brine (2×100 mL) and concentrated to give ether 22b (3.3g, 87% yield).

Step 2:

Neat tributyltin hydride (2.3 mL, 8.8 mmol) is added to a solution ofaryliodide 22b (2.0 g, 7.3 mmol) and AIBN (120 mg, 0.73 mmol) in PhMe(40 mL) and the reaction is then stirred at reflux under N₂. After 1 h,the reaction is concentrated to dryness and the crude product purifiedby CombiFlash® Companion to provide dihydrobenzofuran 22c (785 mg, 73%yield).

Step 3:

Step 3 is comprised of a sequence of synthetic steps identical to steps10 and 11 of Example 15 to provide boronic ester 22d.

Example 23 Synthesis of Boronate Fragment 23c

Step 1:

Neat Tf₂O (0.56 mL, 3.3 mmol) is added dropwise to a cooled (0° C.)solution of phenol 23a (350 mg, 2.1 mmol; prepared according to Doi etal Bull. Chem. Soc. Jpn. 2004 77, 2257-2263) and pyridine (0.91 mL, 11mmol) in DCM (10 mL) under an Ar atmosphere. The reaction is allowed towarm to RT and then is stirred for 2 h. The reaction is quenched by theaddition of a 10% citric acid solution (20 mL) and extracted with DCM(3×20 mL). The combined organic layers are washed with water (20 mL),dried over MgSO₄, filtered and concentrated to dryness. The crudeproduct is purified by CombiFlash® Companion to provide triflate 23b(512 mg, 82% yield).

Step 2:

A solution of the triflate 23b (510 mg, 1.7 mmol),bis[pinocolato]diborane (560 mg, 2.2 mmol) and potassium acetate (500mg, 5.1 mmol) in DMF (18 mL) is degassed with Ar for 5 min followed bythe addition of the PdCl₂dppf-DCM complex (140 mg, 0.17 mmol). Thereaction mixture is then degassed for an additional 5 min before beingheated to 100° C. by microwave irradiation for 10 min. The reaction isthen cooled to RT. The crude reaction mixture is diluted with EtOAc (60mL) and washed with brine (3×60 mL). The organic layer is dried overMgSO₄, filtered and concentrated. The crude mixture is further purifiedby CombiFlash® Companion to afford boronic ester 23c (200 mg, 42%yield).

Example 24 Synthesis of Boronate Fragment 24b

Step 1:

Compound 24b is prepared from 24a following a synthetic sequenceidentical to steps 1 to 6 of Example 12.

Example 25 Synthesis of Boronate Fragment 25b

Step 1:

Compound 25b is prepared from 25a following a synthetic sequenceidentical to steps 1 to 6 of Example 12.

Example 26 Synthesis of Boronate Fragment 26b

Step 1:

Compound 26b is prepared from 26a following a synthetic sequenceidentical to steps 1 to 6 of Example 12.

Example 27 Synthesis of Boronate Fragment 27b

Step 1:

Compound 27b is prepared from 27a following a synthetic sequenceidentical to steps 1 to 6 of Example 14.

Example 28 Synthesis of Boronate Fragment 28b

Step 1:

Compound 28b is prepared from 28a following a synthetic sequenceidentical to steps 1 to 8 of Example 6.

Example 29 Synthesis of Boronate Fragment 29b

Step 1:

Compound 29b is prepared from 29a following a synthetic sequenceidentical to steps 1 to 6 of Example 14.

Example 30 Synthesis of Boronate Fragment 30b

Step 1:

Compound 30b is prepared from 30a following a synthetic sequenceidentical to steps 2 and 3 of Example 18.

Example 31 Synthesis of Boronate Fragment 31b

Step 1:

Compound 31b is prepared from 31a following a synthetic sequenceidentical to steps 9 to 11 of Example 15.

Example 32 Synthesis of Boronate Fragment 32b

Step 1:

Compound 32b is prepared from 32a following a synthetic sequenceidentical to steps 5 to 6 of Example 17.

Example 33 Synthesis of Boronate Fragment 33b

Step 1:

Compound 33b is prepared from 33a following a synthetic sequenceidentical to steps 1 and 4 of Example 11.

Example 34 Synthesis of Boronate Fragment 34f

Step 1:

Benzyl bromide (25 mL, 210 mmol) followed by potassium carbonate (44 g,320 mmol) are added to a solution of 2-methylresorcinol 34a (38 g, 310mmol) dissolved in DMF (1 L). The reaction is stirred overnight, dilutedwith EtOAc (2 L) and washed with water (3×2 L). The organic layer isdried over Na₂SO₄ and concentrated to dryness. The crude product ispurified by CombiFlash® Companion to obtain benzyl ether 34b (18.6 g,39% yield).

Step 2:

Allyl bromide (3.0 mL, 35 mmol) followed by potassium carbonate (6.5 g,47 mmol) are added to a solution of phenol 34b (5 g, 23 mmol) dissolvedin DMF (100 mL). The reaction is stirred overnight, diluted with EtOAc(500 mL) and washed with water (3×500 mL). The organic layer is driedover Na₂SO₄ and concentrated to dryness. The crude product is purifiedby CombiFlash® Companion to obtain benzyl ether 34c (4.4 g, 75% yield).

Step 3:

Compound 34d is prepared from 34c following a synthetic sequenceidentical to steps 2 to 4 of Example 12.

Step 4:

Benzyl ether 34d and Pd—C (10% w/w, 100 mg, 0.094 mmol) are combined inEtOAc (5 mL) and the flask is evacuated and backfilled with a H₂atmosphere (balloon). After stirring for 3 h, the reaction is filteredthrough Celite® (EtOAc washing) and the filtrated concentrated to givephenol 34e (145 mg, 95% yield).

Step 5:

Compound 34f is prepared from 34e following a synthetic sequenceidentical to steps 5 to 6 of Example 17.

Example 35 Synthesis of Boronate Fragment 35e

Steps 1 through 4 are done in analogy to steps 3 through 6 from Example17.

Example 36 Synthesis of Boronate Fragment 36d

Step 1:

4-bromo-3-nitrotoluene 36a (5.0 g, 22.9 mmol) is dissolved in 50 mLethyl acetate and solid tin(II) chloride dihydrate (20.0 g, 86.9 mmol)is added. The mixture is heated under nitrogen atmosphere at 70° C. for2 h (note: temporary overheating to 100° C. is observed! Caution shouldbe exercised!). The mixture is cooled down and is poured into 200 mL ofice-water. 5% aqueous NaHCO₃ (50 mL) solution is added (rapid foaming!),followed by 10 N aqueous NaOH to bring the pH ˜7-8. Large volume ofgelatinous yellowish precipitate is formed. This heterogeneous mixtureis shaken with EtOAc (200 mL) and the mixture is centrifuged in 50 mLportions, resulting in good separation of a yellowish solid. The clearsupernatant is decanted and is extracted with EtOAc. Combined organicphase is washed with brine, dried over sodium sulphate, filtered andconcentrated under vacuum to give an orange oily residue. This residueis re-dissolved in 100 mL of ether and the solution is washed with 10%Na₂CO₃ (20 mL) followed by 2.5 M aqueous NaOH (20 mL). The dark brownorganic solution is then stirred with MgSO₄ and active charcoal andfiltered to give a light yellow solution, which darkened rapidly onstanding in open flask. The solvent is removed under vacuum to give thedesired compound 36b as a brown-red oil which is used in the next stepwithout further purification (3.31 g, 78% yield).

Step 2:

A mixture of compound 36b (3.3 g, 17.7 mmol), glycerin (3.3 g, 35.5mmol), nitrobenzene (2.2 g, 17.7 mmol) and 75% aqueous sulfuric acid (10mL, 138 mmol) is stirred at 150° C. for 3 h (mixture turns black andviscous). The reaction mixture is cooled down, poured into ice-water(200 mL) and 10 N aqueous NaOH is added (30 mL, 300 mmol). The blackmixture is then shaken with EtOAc (100 mL) and is centrifuged in 50 mLportions. The upper EtOAc layers are combined and the bottom aqueouslayers containing the black tar are shaken with EtOAc andre-centrifuged. All EtOAc extracts are combined, washed with brine,dried over Na₂SO₄, filtered and concentrated under vacuum to give abrown-red oil. This material is chromatographed on 80 g silica gelcolumn (CombiFlash® Companion apparatus, hexane-EtOAc gradient). Thefractions containing the compound are concentrated under vacuum toafford compound 36c as a white solid (3.26 g, 83% yield).

Step 3:

To a cooled (−78° C.) solution of compound 36c (500 mg, 2.25 mmole) inanhydrous Et₂O (20 mL), is added over 5 min under an Ar atmosphere a 1.6M solution of n-BuLi in hexane (3.5 mL, 5.60 mmol). The mixture isstirred at −78° C. for 50 min, triisopropylborate (2.00 mL, 8.55 mmol)is then added dropwise and the mixture is stirred for 2 h at thattemperature. The mixture is slowly allowed to reach RT over a 2 h periodand it is poured into 1 M aqueous HCl (30 mL). The mixture istransferred into a separatory funnel, the organic layer is separated andthe aqueous layer is washed with Et₂O. The aqueous layer is thentransferred into a 500 mL Erlenmeyer flask and the pH of the solution isadjusted to 6.3 (measured with a pH meter) by slowly adding a saturatedsolution of NaHCO₃ in water (˜25 mL, careful: foaming). The suspensionis filtered off and the separated light-beige solid is washed with waterand dried under high vacuum. This crude product (383 mg) is trituratedwith Et₂O/hexanes to give a first crop of the desired compound 36d as afree base (120 mg, 28% yield). The mother liquors are concentrated undervacuum and are purified by reversed-phase HPLC using a CH₃CN/H₂Ogradient containing 0.06% TFA (ODS-AQ, C-18 column, 75×30 mm, 5-μmparticle size). After lyophilization, a second crop of compound 36d isobtained as a TFA salt (102 mg, 15% yield), (total yield: 43%).

Example 37 Synthesis of Boronate Fragment 37d

Step 1:

1-bromo-4-chloro-2-nitrobenzene 37a is transformed to compound 37b usingthe procedure of example 36b, except for the fact that Et₂O is used forthe extractions instead of EtOAc.

Step 2:

Compound 37b (4.2 g, 20.3 mmol) is melted at 50° C. in a 100 mLround-bottomed flask containing a stirring bar and immersed in an oilbath. A solution of zinc chloride (700 mg, 5.03 mmol) and ferricchloride (540 mg, 3.25 mmol) in water (3.3 mL) is added in one portionfollowed by absolute EtOH (20 mL). The flask is stoppered with a rubbersepta and a needle is inserted to avoid any pressure build-up. Themixture is warmed to 80° C. and acrolein (1.68 mL, 24.4 mmol) is addedvia a syringe pump over a 2 h period. After the addition, the mixture isstirred at 80° C. for 1 h and an additional amount of solid ferricchloride is added (4.1 g, 25.3 mmol). The mixture is stirred at 80° C.for an extra 24 h and then concentrated under vacuum to give asemi-solid residue. Water (200 mL) is added followed by a 10 N aqueoussolution of NaOH (20 mL) and DCM (200 mL). After shaking the mixture fora few min, the solid is filtered over a pad of Celite® and the filtrateis transferred into a separatory funnel. The organic layer is separatedand the aqueous layer is extracted with DCM. The combined organicextracts are washed with brine, dried (Na₂SO₄), filtered andconcentrated under vacuum to give a brown solid. This solid istriturated in hot CH₃CN and filtered. The solid is discarded and thefiltrate is concentrated under vacuum to give a brown semi-solid (2.3g). This material is purified on a CombiFlash® Companion apparatus on 40g silica gel column eluted with EtOAc/hexanes gradient. Afterevaporation of the solvent under vacuum, the desired compound 37c isisolated as a yellow solid (390 mg, 8% yield).

Step 3:

Compound 37c is transformed to compound 37d using the procedure ofexample 36d.

Example 38 Synthesis of Boronate Fragment 38c

Step 1:

2-bromoaniline 38a is transformed to compound 39b using the procedure ofexample 37c except that methyl vinyl ketone is used instead of acrolein.

Step 2:

Compound 38b is transformed to compound 38c using the procedure ofexample 36d.

Example 39 Synthesis of Boronate Fragment 39k

Reference: Feliu, L.; Ajana, W.; Alvarez, M.; Joule, J. A. Tetrahedron1997, 53, 4511.Step 1:

Meldrum's acid 39b (47.04 g, 326 mmol) is dissolved in trimethylorthoformate (360 mL) and refluxed for 2 h. Then 2,5-dimethoxy aniline39a (50 g, 326 mmol) is added and the mixture is refluxed for an extra 5h. The reaction mixture is cooled down to RT and the solid which formedupon cooling is collected by filtration. It is further crystallized fromMeOH to afford compound 39c as a yellow solid (63 g, 63% yield).

Step 2:

Compound 39c (62.00 g, 202 mmol) is dissolved in diphenyl ether (310 mL)and refluxed at 240° C. for 30 min. The mixture is then cooled down toRT and n-hexane is added, which causes a brown precipitate to form. Thissolid is separated by filtration and is washed with n-pentane andn-hexane to remove non-polar impurities and the remaining dark brownsolid (compound 39d) is used as is in the next step (27 g, 65% yield).

Step 3:

A mixture of compound 39d (30.0 g, 146 mmol), DMAP (3.75 g, 30.7 mmol)and 2,6-lutidine (24.4 mL; 208 mmol) in DCM (1.4 L) is cooled to 0° C.and Tf₂O (29.6 mL, 175 mmol) is added slowly at 0° C. The resultingmixture is stirred at 0° C. for 2 h and at RT for 1 h. It is thendiluted with DCM, washed with H₂O and brine and dried (Na₂SO₄). Thesolvent is removed under reduced pressure and the residue is purified byflash chromatography on silica gel (20% EtOAc/petroleum ether). Thedesired compound 39e is isolated as a yellow solid (35 g, 70% yield).

Step 4:

A mixture of diisopropylethyl amine (46.5 mL, 267 mmol) in dry DMF (250mL) is degassed with argon for 30 min and is added to a mixture ofcompound 39e (30.0 g, 89.0 mmol), triphenylphosphine (7.70 g, 29.4mmol), tris(dibenzylideneacetone)di-palladium(0)-chloroform adduct (9.21g, 8.9 mmol). The resulting mixture is stirred for 5 min at 0° C. andTMS acetylene (13.4 g, 136 mmol) is added dropwise. The temperature israised to RT and the mixture is stirred for 4 h. Diethyl ether and wateris added, the aqueous layer is separated and washed with diethyl ether.The combined organic layers are washed with H₂O and brine. After dryingon Na₂SO₄, the solvent is removed under reduced pressure and the residueis purified by flash chromatography on silica gel (30% EtOAc/petroleumether). Compound 39f is isolated as a yellow solid (18 g, 70% yield).

Step 5:

A solution of ceric ammonium nitrate (42.3 g, 77.2 mmol) in H₂O (47 mL)is added under argon atmosphere to a solution of compound 39f (11.0 g,38.3 mmol) in acetonitrile (366 mL). The reaction mixture is degassedwith argon for 10 min and the mixture is stirred at RT for 20 min. Wateris then added and the solution is extracted with DCM. The organicextracts are combined, washed with H₂O, brine and dried (Na₂SO₄). Thesolvent is removed under reduced pressure and the residue is purified byflash chromatography on silica gel (40% EtOAc/petroleum ether). Thedesired compound 39g is isolated as a yellow solid (5.0 g, 52% yield).

Step 6:

Compound 39g (1.80 g, 7.1 mmol) is taken in distilled acetic acid (72mL) under argon atmosphere. Ammonium chloride (7.55 g, 141 mmol) isadded and the reaction is refluxed for 45 min. The reaction mixture iscooled to RT, H₂O is added and the solution is washed with EtOAc. Theaqueous layer is neutralized with a saturated aqueous solution of NaHCO₃and is extracted with EtOAc. The combined organic extracts are washedwith H₂O, brine and dried (Na₂SO₄). The solvent is removed under reducedpressure to afford compound 39h as a brown solid (250 mg, 20% yield).

Step 7:

Compound 39h (230 mg, 1.24 mmol) is dissolved in absolute EtOH (11 mL)and 10% palladium on carbon is added (46 mg) under nitrogen atmosphere.The mixture is stirred for 15 h under one atmosphere of hydrogen. Thereaction is degassed with nitrogen, filtered through Celite®, and theCelite® bed is washed with an EtOH—CHCl₃ mixture. The solvent is removedunder reduced pressure to give compound 39i as a brown sticky solid (200mg, 86% yield).

Step 8:

Compound 39i (600 mg, 3.21 mmol) is taken in dry DCM (30 mL) undernitrogen atmosphere. The solution is cooled to 0° C. and triethylamine(0.89 mL, 6.42 mmol) is added dropwise followed by Tf₂O (0.65 mL, 3.87mmol). The temperature is raised to RT and the reaction mixture isstirred for 2 h. The mixture is diluted with DCM and is washed with H₂O,brine and dried (Na₂SO₄). The solvent is removed under reduced pressureto afford a residue which is purified by flash chromatography (10%EtOAc/hexane). Compound 39j is isolated as a brown solid (630 mg, 61%yield).

Step 9:

In a dry (oven-dried for 30 min.) 5-mL glass microwave vessel containinga magnetic stirring bar, are added compounds 39j (250 mg, 0.078 mmol),bis(pinacolato)diborane (250 mg, 0.098 mmol), anhydrous potassiumacetate (150 mg, 1.51 mmol), Pd(PCy₃)₂ (62.0 mg, 0.091 mmol) andanhydrous, deoxygenated (argon bubbling for 30 min) 1,4-dioxane (4 mL).The vial is capped tightly with a septum-cap and the vessel is flushedwith argon. The mixture is stirred at 95° C. (oil bath temperature)under an atmosphere of argon for 16 h. The reaction mixture is thenconcentrated under vacuum, the brown oily residue is dissolved inglacial AcOH (7 mL) and is filtered via 45 μm membrane filter. The darkbrown solution is divided into 5×1.5 mL portions and is injected on anautomatic preparative reversed-phase HPLC-MS apparatus (CH₃CN/H₂Ogradient containing 0.06% TFA, ODS-AQ, C-18 column, 50×19 mm, 5-μmparticle size). The collected fractions are lyophylized to give thedesired compound 39k as a yellow amorphous solid (115 mg, 45% yield forthe TFA salt).

Example 40 Synthesis of Compound 1035

Step 1:

The 7-bromo-4-iodoquinoline 40a is synthesized from 3-bromoaniline usingthe same protocols as those described for the preparation ofiodoquinoline fragment 1i in Example 1.

Step 2:

The 7-bromo-4-iodoquinoline 40a (2.9 g, 5.9 mmol) is combined withboronate 10g (2 g, 6.8 mmol), potassium carbonate (2.4 g, 17.6 mmol),and Pd[PPh₃]₄ (680 mg, 0.59 mmol) in DMF (24 mL). The solution isdegassed (Ar) and then heated at 105° C. for 5 h. The cooled solution isdiluted with EtOAc (200 mL) and washed with brine (3×). The organicphase is dried (MgSO₄), filtered and concentrated to dryness. Theresidue is purified by CombiFlash® Companion to afford compound 40b as amixture of atropisomers (670 mg, 21% yield).

Step 3:

To a solution of bromide 40b (670 mg, 1.26 mmol) in THF (30 mL) is addedvinyltributyltin (0.42 mL, 1.38 mmol). Following degassing by bubblingAr for 10 min under sonication, PdCl₂-[PPh₃]₂ (0) (88 mg, 0.125 mmol) isadded followed by degassing for another 5 min. The reaction mixture isstirred at 75° C. for 20 h before being concentrated to dryness. Theresidue is purified by CombiFlash® Companion to afford compound 40c (400mg, 66% yield) which is used as in the following step.

Step 4:

To a solution of compound 40c (339 mg, 0.7 mmol) in THF (8 mL) and water(4 mL) at RT is added OsO₄ (177 μL, 2.5% soln in t-butanol, 0.014 mmol)followed by NMO (93 mg, 0.8 mmol). The reaction is stirred for 16 h butis not complete. The same quantities of OsO₄ and NMO are again added andstirring continues for an additional 1 h. Sodium periodate (196 mg, 0.92mmol) is added to generate the intermediate aldehyde. The reactionmixture is poured into a saturated solution of aqueous Na₂S₂O₃ and water(50 mL) is added before it is extracted with DCM (3×). The solvent isfiltered using a phase separator filter and concentrated. The residue isdissolved in MeOH (10 mL) and treated with NaBH₄ (80 mg, 2.1 mmol) at RTfor 1 h to give the crude alcohol. A saturated solution of NH₄Cl isadded, followed by water (50 mL) and the mixture then is extracted withDCM (3×). The phases are separated using a phase separator filter andthe organic phase is concentrated. The residue is purified using theCombiFlash® Companion to afford the alcohol 40d (171 mg, 50% yield).

Step 5:

To a solution of alcohol 40d (171 mg, 0.35 mmol) in anhydrous DCM (5 mL)at RT is added anhydrous DMF (1 drop) followed by thionyl chloride (51.5μL, 0.7 mmol). The resulting solution is stirred for 1 h before beingdiluted with DCM (5 mL) and then washed with a saturated solution ofNaHCO₃ (5 mL). After being stirred for 1 min, the mixture is passedthrough a phase separator filter and concentrated to afford chloride 40e(160 mg, 90% yield) as a pale yellow solid, which is used as is in thefollowing step.

Step 6:

In a vial suitable for microwave, the following are dissolved inanhydrous DMF (2 mL); benzyl chloride 40e (40 mg, 0.08 mmol),4-pyridylboronic acid (24 mg, 0.2 mmol), K₃PO₄ (51 mg, 0.24 mmol),Pd(OAc)₂ (4 mg, 0.018 mmol), and triphenylphosphine (8.5 mg, 0.032mmol). The vial is capped and is degassed by bubbling Ar undersonication for 5 min before being heated at 120° C. for 20 min in amicrowave. The crude mixture is diluted with EtOAc (200 mL) and washedwith brine (3×). The phases are filtered through a phase separatorfilter and concentrated to dryness. The residue is purified byCombiFlash® Companion to afford the mixture of atropisomeric methylesters (33 mg, 76% yield) as a pale yellow oil. A solution of thismixture (33 mg) in THF (2 mL) and MeOH (1 mL) and 5N NaOH (72 μL, 0.36mmol) is stirred at 45° C. for 3 h. Acetic acid is added until thesolution is acidic and the resulting mixture is then concentrated. Finalpurification to separate the atropisomers (diastereomers) is performedby preparative HPLC to afford after lyophilization compound 1035 (1.25mg, 4% yield) as an amorphous solid.

It would be obvious to those skilled in the art that intermediates 40a,40b and 40e can be used to make a variety of other compounds.Intermediate 40a can be coupled to any of the boronate fragmentsdescribed herein in Examples 4-39 via Suzuki coupling reaction to giveintermediates analogous to 40b having different R⁴ substituents.Intermediates 40b and 40e can then be further modified in a variety ofways that would be evident to those skilled in the art, includingdirectly attached amines and benzylic-type amines derivatives viaBuchwald-type coupling or direct alkylation, respectively, with thecorresponding amine; the details of the synthesis of two compounds, 1074(Example 41) and 1071 (Example 42) are described below.

Example 41 Synthesis of Compound 1074

In a vial suitable for microwave reactions is added bromide 40b (15 mg,0.028 mmol), acetyltrimethylammonium bromide (2.1 mg, 0.006 mmol),Pd[(tBu)₃P]₂ (2.6 mg, 0.003 mmol), 1-methylpiperazine (4 μL, 0.037mmol), and a solution of 2 M sodium carbonate (21 μL, 0.042 mmol). Thereagents are dissolved in toluene (1.0 mL) before being capped and thensubmitted directly to the following microwave conditions: 20 min at 145°C. The mixture is concentrated to dryness and purified by CombiFlash®Companion to afford the methyl esters of the atropisomeric mixture (8mg, 52% yield) as a pale yellow oil. This mixture is dissolved in THF (3mL) and MeOH (1.5 mL) before being treated with 5N NaOH (17 μL, 0.09mmol). The solution is heated to 55° C. for 16 h before being acidifiedwith AcOH and concentrated to dryness. The mixture is purified bypreparative HPLC to separate the atropisomers (diastereomers) and affordafter lyophilization, compound 1074 as a yellow amorphous solid (1 mg,12% yield).

Example 42 Synthesis of Compound 1071

To a solution of chloride 40e (25 mg, 0.05 mmol) in DMF (3 mL) is addedKI (2.5 mg, 0.015 mmol), 1-methylpiperazine (8.8 μL, 0.08 mmol), andtriethylamine (17 μL, 0.12 mmol). The reaction mixture is stirred at RTfor 24 h. The reaction mixture is diluted with EtOAc (40 mL) and washedwith brine (3×). The mixture is filtered through a phase separatorfilter and concentrated to dryness to afford the atropisomeric mixtureof esters (28 mg, 100% yield) as a pale yellow oil. The mixture ofesters is dissolved in THF (3 mL) and MeOH (1.5 mL) and 5N NaOH (59 μL,0.3 mmol) is added. The solution is heated to 55° C. for 16 h beforebeing acidified with AcOH and concentrated. The atropisomers(diastereomers) are separated by preparative HPLC to afford (afterlyophilization) compound 1071 as orange solid (8.5 mg, 30% yield).

Example 43 Synthesis of Compound 1057

Step 1:

8-bromo-4-iodoquinoline 43a is synthesized from 2-bromoaniline using thesame protocols as those described for the preparation of iodoquinolinefragment 1i in Example 1.

Step 2:

In a suitable microwave vessel, quinoline 43a (740 mg, 1.5 mmol) isadded to boronic ester 10g (511 mg, 1.73 mmol), Pd[PPh₃]₄ (347 mg, 0.3mmol) and K₂CO₃ (623 mg, 4.5 mmol) in DMF (8 mL). The vessel is sealedand heated for 25 min at 135° C. The cooled reaction mixture is filteredthrough Celite® and the filtrate is diluted with EtOAc. The organicphase is washed with water, brine, dried (MgSO₄), filtered andconcentrated under vacuum. The crude product is purified by CombiFlash®Companion to afford a mixture of esters 43b (426 mg, 53% yield, mixtureof two atropisomers).

Step 3:

A mixture of bromide 43b (60 mg, 0.011 mmol), phenylboronic acid (19.2mg, 0.016), Pd[PPh₃]₄ (26 mg, 0.02 mmol) and K₂CO₃ (47 mg, 0.034 mmol)in DMF (1.5 mL) and water (0.2 mL) is heated to 125° C. for 13 min in amicrowave. The cooled reaction mixture is filtered through Celite® andthe filtrate is diluted with EtOAc. The organic phase is washed withwater, brine, dried (MgSO₄), filtered and concentrated under vacuum. Thecrude product is purified by CombiFlash® Companion to give a crudeproduct mixture (32.8 mg, 55% yield). This mixture is dissolved inTHF/MeOH (3 mL/1.5 mL) and treated with 1.0 N NaOH (1 mL, 1.0 mmol). Thereaction mixture is stirred at 60° C. for 4 h before being acidified topH 4 with 1.0 N HCl. The mixture is then extracted with DCM, dried(MgSO₄), filtered and concentrated under vacuum. The residue is purifiedby preparative HPLC to afford after lyophilization compound 1057 as anorange solid (9.9 mg, 31% yield).

Example 44 Synthesis of C-2 Substituted Analogs

Step 1:

The 4-iodoquinoline 1i (3 g, 7.2 mmol) is dissolved in CCl₄ (30 mL)which is subsequently treated with recrystallized NBS (1.4 g, 7.9 mmol)followed by benzoyl peroxide (72 mg, 0.3 mmol). The solution is heatedto 75° C. for 24 h. The solvent is removed and the crude product takenup in EtOAc (250 mL), washed with brine, before being dried (Na₂SO₄),filtered and concentrated to afford the crude product as an amber gum.This material is purified by CombiFlash® Companion to afford bromide 44a(2.5 g, 70% yield).

It is clear for a person skilled in the art that various analogs can beprepared from compound 44a using a variety of appropriate metalalkoxides (in the case of alcohols) or appropriate anions for nitrogenbased nucleophiles; as an example, the synthesis of compound 2005 isshown below

Step 1:

Phenol (19 mg, 0.20 mmol) is dissolved in DMF (1.0 mL) before beingtreated with K₂CO₃ (15 mg, 0.10 mmol). The potassium salt is allowed topre-form over a period of 1 h before a solution of bromide 44a is added(50 mg, 0.10 mmol). The aryl ether is allowed to form overnight at RT.The mixture is taken up in EtOAc (15 mL) and washed with brine beforebeing dried (Na₂SO₄), filtered and concentrated. The crude product ispurified by CombiFlash® Companion to give the aryl ether 44b as acolorless gum (36 mg, 70% yield).

Step 2:

In a microwave vessel is added ether 44b (36 mg, 0.07 mmol), the boronicester 11d (24 mg, 0.09 mmol), K₂CO₃ (29 mg, 0.21 mmol) and the catalystPd(PPh₃)₄ (8.3 mg, 0.01 mmol) all dissolved in DMF/H₂O (1 mL/0.1 mL).The vessel is capped and submitted to microwave conditions at 110° C.for 15 min. The reaction mixture is diluted with EtOAc and subsequentlywashed with water. The organic phase is further washed with brine, dried(MgSO₄), filtered and concentrated. The material is purified byCombiFlash® Companion to afford the methyl ester of the desired product(23 mg, 63% yield) as a white solid. This material is dissolved in THF(1 mL) and MeOH (0.6 mL) and NaOH (1 N, 0.33 mL, 0.33 mmol) is added.The mixture is stirred at 50° C. for 16 h. The mixture is concentratedin vacuo before being purified by reversed phase preparative HPLC toafford after lyophilization compound 2005 as a yellow amorphous solid(13.5 mg, 60% yield).

It would be obvious to those skilled in the art that intermediate 44acan be used with other nucleophiles to displace the primary bromide (asin the preparation of 44b from 44a), followed by Suzuki coupling withany boronate fragment described in this application to produce a varietyof other compounds (for example, the production of compound 2005 from44b).

Example 45 Synthesis of Compound 1046

Step 1:

Triflic anhydride (190 μL, 1.13 mmol) is added via syringe over 1 min toa stirred mixture of amide 45a (250 mg, 1.0 mmol) and 2-chloropyridine(130 μL, 1.4 mmol) in DCM (2 mL) at −78° C. After 5 min, the reactionflask is placed in an ice-water bath and warmed to 0° C. Alkyne 2c (232mg, 0.70 mmol) in DCM (1 mL) is added via syringe. The resultingsolution is allowed to warm to RT. After stirring for 30 min, Et₃N (1mL) is added and the mixture partitioned between DCM (50 mL) and brine(50 mL). The organic layer is washed with brine (50 mL), dried overNa₂SO₄ and concentrated. The residue is then purified by CombiFlash®Companion giving quinoline 45b (380 mg, 97% yield).

Step 2:

Quinoline 45b (380 mg, 0.68 mmol) is dissolved in TFA/water (10:1, 10.5mL) and the reaction is stirred at RT. After 30 min, the reactionmixture is concentrated under reduced pressure, diluted with saturatedNaHCO₃ (5 mL) and extracted with DCM (3×10 mL). The combined organiclayers are dried over Na₂SO₄ and concentrated to give diol 45c (299mg, >99% yield).

Step 3:

Trimethylacetyl chloride (100 μL, 0.81 mmol) is added to a 0° C.solution of diol 45c (299 mg, 0.68 mmol) and Et₃N (280 μL, 2.0 mmol) inDCM (3.8 mL). The reaction is allowed to come to RT and stir overnight.The reaction is quenched with water (10 mL) and washed with EtOAc (10mL). The organic layer is dried over Na₂SO₄ and concentrated. Themixture is purified by CombiFlash® Companion to give ester 45d (85 mg,24% yield).

Step 4:

One drop of 70% perchloric acid is added to a stirred solution ofalcohol 45d (85 mg, 0.161 mmol) dissolved in tert-butyl acetate (1.8 mL)at RT and the mixture stirred overnight. The reaction is quenched byaddition of saturated NaHCO₃ (5 mL) and the mixture extracted with EtOAc(5 mL). The organic layer is dried over Na₂SO₄, filtered and the solventevaporated. The residue is purified by CombiFlash® Companion to givetent-butyl ether 45e (40 mg, 43% yield).

Step 5:

LiBH₄ in THF (2 M, 69 μL, 0.14 mmol) is added to a solution of ester 45e(40 mg, 0.069 mmol) dissolved in THF (1 mL) and the reaction mixture isstirred overnight at RT. Excess reagent is quenched with HCl (threedrops, lots of effervescence) and the mixture neutralized with NaHCO₃(10 mL) and extracted with EtOAc (3×10 mL). The combined organic layersare dried over Na₂SO₄ and concentrated to give crude alcohol 45f (27 mg,79% yield), which was used directly in the next step.

Step 6:

Dess-Martin periodinane (30 mg, 0.07 mmol) is added to a solution ofalcohol 45f (27 mg, 0.54 mmol) dissolved in DCM (0.4 mL). After 2 h, thereaction mixture is then applied to a plug of SiO₂ (1.5×1 cm) and theproduct eluted with 1:1 hexanes/EtOAc (20 mL). The filtrate isevaporated to give the crude aldehyde which is then dissolved in 1:1THF/tBuOH (2 mL) and 2,3-dimethyl-2-butene (1M in THF, 0.5 mL, 0.5 mmol)is added. A separate solution of NaClO₂ (39 mg, 0.44 mmol) and NaH₂PO₄(32 mg, 0.27 mmol) in water (1 mL) is added to the first solution andthe reaction stirred at RT. After 20 min, the reaction is diluted withwater (5 mL) and extracted with EtOAc (3×10 mL). The organic layer isdried over Na₂SO₄ and concentrated. The residue is purified bypreparative HPLC to give carboxylic acid 1046 (6 mg, 20% yield).

Example 46 Alternative Synthesis of Boronate Fragment 39K

Step 1:

1,3-acetonedicarboxylic acid 46a (30 g, 205.3 mmol) is added in portionsto acetic anhydride (55 g, 587.7 mmol) and the mixture is stirred at 35°C. for 23 h. The mixture is filtered and the filtrate is diluted withbenzene (200 mL) and the solution stored at 5° C. for 3 h. Thesuspension formed is filtered and the solid is dried under vacuum togive compound 46b as a pale yellow solid (26.9 g, 70% yield).

Step 2:

To a stirred solution of aniline 46c (7.5 g, 44 mmol) in AcOH (50 mL) isadded 46b (8.0 g, 40 mmol) portionwise. Following addition, the reactionmixture is warmed to 35° C. After 2 h, the reaction mixture is cooled toRT and poured in ice/water (600 mL). The resulting precipitate isisolated by filtration, rinsed with water (100 mL) and dried undervacuum to give 46d (9.1 g, 61% yield).

Step 3:

Compound 46d (5.7 g, 15.4 mmol) is added portionwise to concentratedsulfuric acid (20 mL) at RT, temperature of the reaction mixture is keptbelow 30° C. during addition. The mixture is stirred at RT for 30 minand then poured in ice/water (400 mL). The resulting precipitate isisolated by filtration, rinsed with water and dried under vacuum to give46e (3.5 g, 72% yield) as a white solid.

Step 4:

The borane solution (1.0 M in THF, 10.5 ml, 10.5 mmol) is added dropwiseto an ice cold solution of quinolone 46e (1.5 g, 4.8 mmol) in dry THF(40 mL) under a N₂ atmosphere. After the addition, the reaction isallowed to warm to RT and stirred for 22 h (reaction not completed byHPLC, 15% starting material). An extra equivalent of BH₃ is added at 0°C. and the reaction mixture is heated to 45° C. for 2 h. The reactionmixture is carefully quenched with 1.0 N NaOH (10 mL) and THF is removedunder vacuum. The mixture is poured in EtOAc (100 mL) and the desiredcompound crashed out of the solution under these conditions. The solidrecovered by filtration is dried under vacuum to give compound 46f as agrey solid (1.1 g, 79% yield).

Step 5:

To a solution of 46f (1.1 g, 3.8 mmol) in DCM (60 mL) at −78° C. isadded dropwise a 1.0 M BBr₃ solution (23 mL, 23 mmol). The cooling bathis removed after 1 h and the mixture is stirred at RT for 16 h (by HPLC,˜30% cyclized product 46h is formed). The mixture is poured in ice/water(100 mL) and the white precipitate that formed is filtered and driedunder vacuum to give 46g (773 mg, 71% yield).

Step 6:

To a solution of compound 46g (773 mg, 2.27 mmol) in THF (30 mL) isadded PPh₃ (928 mg, 3.5 mmol) followed by DIAD (0.69 ml, 3.5 mmol)(dropwise) and the solution is stirred at RT for 2 h. The reactionmixture is concentrated under vacuum and the crude product is directlyadded portionwise to POCl₃ (2 mL) at RT. The reaction mixture is stirredat 100° C. for 45 min and then cooled to room temperature. The mixtureis concentrated under vacuum (to remove POCl₃) and the crude product isdiluted with DCM. The organic phase is washed with 1.0 N NaOH, water,and brine, dried (MgSO₄), filtered and concentrated under vacuum. Thecrude product is purified by CombiFlash® Companion (Hexanes/EtOAc 9/1 to1/1) to give 46h as a pale yellow solid (445 mg, 91% yield).

Step 7:

To a solution of chloroquinoline 46h (30 mg, 0.1 mmol) in TFA (1 mL) isadded zinc (34 mg; 0.5 mmol). The reaction mixture is stirred at RT for16 h. The mixture is filtered, concentrated under vacuum, then dilutedwith 1.0 N NaOH (5 mL) and extracted with DCM (3×). The combined organicextracts are washed with water and brine, dried (MgSO₄), filtered andconcentrated under vacuum. The crude product was purified by combi flash(Hexanes/EtOAc 6/4 to 4/6) to give 46i as a pale yellow solid (26 mg,quantitative yield).

Step 8:

The reaction is done following a similar procedure as described in step9 of example 39 except starting with 46i and using Pd(Ph₃)₄ as catalystto give 39k as a white solid.

Example 47 Synthesis of Compound 1093

Step 1:

Iodoquinoline 47a is synthesized from aniline 46a using the sameprotocols as those described for the preparation of iodoquinolinefragment 1i in Example 1.

Step 2:

Reaction is carried out exactly as described in step 2 of example 43using iodo 47b and boronic acid 39k to give compound 1093.

Example 48 Synthesis of Compound 1015 and 1016

Step 1:

A 1.93 M phosgene solution in toluene (106.9 mL, 206.3 mmol) is added toa vigorously stirred suspension of anthranilate 48a (25.6 g, 165 mmol)in toluene (150 mL) in a pressure bottle. The reaction vessel is sealedand heated to 100° C. behind safety shield overnight. An additionalamount of phosgene solution (42.7 mL; 82.5 mmol) is added to the cooledmixture and the reaction mixture is heated to 100° C. for an additional4 h then is allowed to cool slowly to 0° C. The resulting suspension isfiltered, the solid is washed with cold toluene and air dried overnightto give 48b (28.1 g, 94% yield) as a white solid.

Step 2:

A solution of 48b (28.1 g, 155 mmol) and DMAP (1.89 g, 15.5 mmol) inMeOH (500 mL) is heated at reflux for 24 h. The cooled reaction mixtureis concentrated under reduced pressure and diluted with EtOAc (200 mL).The resulting solution is washed twice with phosphate buffer pH 6.0,dried (MgSO₄), filtered and concentrated under reduced pressure to givecompound 48c (26.1 g, 99% yield).

Step 3:

A solution of 48c (26.0 g, 154 mmol), ethyl 3-ethoxybut-2-enoate (25.5g, 161 mmol) and p-TsOH monohydrate (75.3 mg, 0.40 mmol) in o-xylene(500 mL) is heated (bath temp: 158° C.) for 15 h using a Dean-Stark trapto remove the produced EtOH. The mixture is cooled to RT and addedslowly (25 min) to an ice-cold solution of 21% (w/w) NaOEt (60.26 mL,161.5 mmol) in EtOH. The resulting brownish solution is heated to 80° C.for 4 h. The resulting suspension is allowed to cool to RT and isconcentrated under reduced pressure. Water (400 mL) is added to theresidual solid and the mixture is washed with Et₂O (2×400 mL). Theaqueous phase is cooled to 0° C. and slowly acidified to pH 4 using 1 NHCl. The resulting suspension is filtered and the recovered solid iswashed with dilute HCl (pH 4, 25 mL), dried under reduced pressure togive compound 48d (24.1 g, 63% yield) as a pale yellowish solid.

Step 4:

A mixture of 48d (24.1 g, 96.7 mmol) and POCl₃ (250 mL) is heated atreflux for 1 h. The cooled reaction mixture is concentrated underreduced pressure. The residue is poured into ice-water (500 mL) andstirred vigorously. The pH is adjusted to 6.5 using aqueous 5 N NaOH.The mixture is extracted with EtOAc and the combined organic layers arewashed with brine, dried (MgSO₄), filtered and concentrated underreduced pressure to give compound 48e (25.2 g, 97% yield) as a blacktar. The crude product is used as in next step.

Step 5:

A solution of 1 M DIBAL-H in toluene (200 mL, 200 mmol) is added (45min) to a cold (−78° C.) solution of 48e (25.2 g, 94.1 mmol) in DCM (300mL). The reaction mixture is stirred at RT for 30 min then re-cooled to−78° C. An aqueous 20% Rochelle salt solution (200 mL) is added and themixture is allowed to warm to RT. The resulting suspension is dilutedwith DCM (300 mL) and the layers are separated. The aqueous layer isextracted twice with DCM. The combined organic layers are dried (MgSO₄),filtered and concentrated under reduced pressure. The resulting solid isdried at 50° C. under reduced pressure to give alcohol 48f (15.18 g, 71%yield) as a brown solid.

Step 6:

Et₃N (18.5 mL, 133 mmol) is added to a cool solution of 48f (10.0 g,44.3 mmol) in DMSO (50 mL). Pyridine SO₃ complex (17.6 g, 111 mmol) isnext added to the mixture in small portions over 5 min. The reactionmixture is stirred for 1 h then is poured in ice cold water (400 mL) andthe resulting suspension is filtered. The solid is dissolved in DCM (200ml) and the solution is dried (MgSO₄), filtered and concentrated underreduced pressure to give aldehyde 48g (9.01 g, 91% yield) as a brownsolid.

Step 7:

ZnI₂ (6.42 g, 20.1 mmol) and TMSCN (10.7 mL, 80.5 mmol) are successivelyadded to an ice-cold solution of aldehyde 48g (9.00 g, 40.2 mmol) in DCM(300 mL). The mixture is stirred at 0° C. for 1 h and at RT for 4 h. Thereaction mixture is washed with water, dried (MgSO₄), filtered andconcentrated under reduced pressure to give cyanohydrin 48h (12.0 g, 93%yield) as a tan crystalline solid.

Step 8:

A saturated solution of hydrogen chloride in MeOH (80 mL) is added to asuspension of 48h (12.2 g, 37.8 mmol) in MeOH (20 mL). The reactionmixture is stirred at RT for 2 h. N₂ is bubbled in the mixture for 30min to remove excess HCl. The mixture is concentrated under reducedpressure to give compound 48i (11.1 g, 92% yield) as a tan crystallinesolid.

Step 9:

A solution of 48i (11.05 g, 34.6 mmol) in aqueous 1 N HCl (150 mL) isstirred for 1 h at RT. The reaction mixture is diluted with water (100mL) and filtered over Celite®. The pH of the aqueous filtrate isadjusted to 7.5 using aqueous 5 N NaOH. The solution is extracted twicewith EtOAc. The combined organic layers are washed with brine, dried(MgSO₄), filtered and concentrated under reduced pressure to give methylester 48j (10.2 g, 104% yield) as a tan solid.

Step 10:

Chloroquinoline 48j (10.2 g, 36.0 mmol) is dissolved in a solution of 4N HCl in 1,4-dioxan (100 mL). The solution was concentrated underreduced pressure. A mixture of the resulting HCl salt and NaI (27.0 g,180 mmol) in MeCN (250 mL) is heated at reflux for 1 h. The cooledreaction mixture is diluted with EtOAc (300 mL) and the mixture iswashed with aqueous 5% NaHCO₃ solution and aqueous 10% Na₂S₂O₄ solution.The organic layer is dried (MgSO₄), filtered and concentrated underreduced pressure to give iodoquinoline 48k (11.3 g, 84% yield) as a tansolid.

Step 11:

HClO₄ (1.17 mL, 13.6 mmol) is added to a suspension of 48k (3.40 g, 9.06mmol) in t-butyl acetate (100 mL) and DCM (150 mL). The reaction mixtureis stirred at RT overnight then is diluted with EtOAc (150 mL). Thesolution is washed twice with aqueous 5% NaHCO₃ solution, dried (MgSO₄),filtered and concentrated under reduced pressure. The residue ispurified by flash chromatography (Combi-Flash; EtOAc/hexane) to givet-butylether 481 (2.76 g, 71% yield) as a white solid.

Step 12:

A mixture of ester 48l (5.01 g, 11.6 mmol) and LiOH hydrate (487 mg,11.6 mmol) in THF (30 mL), MeOH (15 mL) and water (15 mL) is heated atreflux for 11 h. The reaction mixture is concentrated under reducedpressure. The residue is successively taken in EtOH (2×150 mL) andtoluene (100 mL) and concentrated under reduced pressure to removetraces of water. The solid is dried under reduced pressure to givelithium salt 48m (5.10 g, 104% yield) as a pale yellow solid.

Step 13:

Pivaloyl chloride (1.43 mL, 11.6 mmol) is added to an ice-cold solutionof 48m (5.08 g, 11.6 mmol) in THF (100 mL). The mixture is stirred at 0°C. for 30 min then cooled to −78° C. (mixed anhydride solution). Asolution of 2.5 M n-BuLi in hexane (4.87 mL, 12.2 mmol) is addeddropwise (until an orange color persisted) to a cold solution (−40° C.)of (R)-(+)-4-benzyl-2-oxazolidinone (2.16 g, 12.2 mmol) andtriphenylmethane (10 mg) in THF (30 mL). The resulting mixture is cooledto −78° C. and rapidly cannulated into the mixed anhydride solutionprepared previously. The reaction mixture is stirred at −78° C. for 30min then is allowed to warm to RT and stirred at this temperature for 30min. Aqueous 5% KHCO₃ solution (4 mL) is added and the mixture isconcentrated under reduced pressure. The residue is diluted with EtOAc(250 mL) and the solution is successively washed with aqueous 5% KHCO₃solution and brine, dried (MgSO₄), filtered and concentrated underreduced pressure. The residue is purified by flash chromatography(Combi-Flash; EtOAc/hexanes) to give the desired diasteroisomer 48n(1.34 g, 20% yield; higher retention time on reverse phase HPLC).

Step 14:

DBU (416 μL, 2.78 mmol) and NaI (1.74 g, 11.6 mmol) are successivelyadded to a cold (−5° C.) solution of oxazolidinone 48n (1.34 g, 2.32mmol) in THF (6 mL) and MeOH (12 mL). After 1 h the reaction mixture isconcentrated under reduced pressure and EtOAc (100 mL) is added. Thesolution is washed with aqueous phosphate buffer pH 6.0 and brine, dried(MgSO₄), filtered and concentrated under reduced pressure. The residueis purified by flash chromatography (Combi-Flash; EtOAc/hexanes) to givemethyl ester 48o (718 mg, 72% yield) as a yellowish crystalline solid.

Step 15:

Reaction is carried out exactly as described in step 2 of example 43using iodo 48o and boronic acid 6i to give compound 1015 and 1016.

Example 49 C8166 HIV-1 Luciferase Assay (EC₅₀)

C8166 cells are derived from a human T-lymphotrophic virus type 1immortalized but nonexpressing line of cord blood lymphocytes (obtainedfrom J. Sullivan) and are highly permissive to HIV-1 infection. The pGL3Basic LTR/TAR plasmid is made by introducing the HIV-1 HxB2 LTR sequencefrom nucleotide −138 to +80 (Sca1-HindIII) upstream of the luciferasegene in the pGL3 Basic Vector (a promoterless luciferase expressionvector from Promega catalogue #E1751) with the gene for blasticidineresistance cloned in. The reporter cells are made by electroporatingC8166 cells with pGL3 Basic LTR/TAR and selecting positive clones withblasticidine. Clone C8166-LTRIuc #A8-F5-G7 was selected by 3 consecutiverounds of limiting dilution under blasticidine selection. Cultures aremaintained in complete media (consisting of: Roswell Park MemorialInstitute medium (RPMI) 1640+10% FBS+10⁻⁵ M β-mercaptoethanol+10 μg/mLgentamycin) with 5 μg/mL blasticidine, however, blasticidine selectionis removed from the cells before performing the viral replication assay.

Luciferase Assay Protocol

Preparation of Compounds

Serial dilutions of HIV-1 inhibitor compounds are prepared in completemedia from 10 mM DMSO stock solutions. Eleven serial dilutions of 2.5×are made at 8× desired final concentration in a 1 mL deep well titerplate (96 wells). The 12^(th) well contains complete media with noinhibitor and serves as the positive control. All samples contain thesame concentration of DMSO 0.1% DMSO). A 25 μL aliquot of inhibitor isadded, to triplicate wells, of a 96 well tissue culture treated clearview black microtiter plate (Corning Costar catalogue #3904). The totalvolume per well is 200 μL of media containing cells and inhibitor. Thelast row is reserved for uninfected C8166 LTRIuc cells to serve as thebackground blank control and the first row is media alone.

Infection of Cells

C8166 LTRIuc cells are counted and placed in a minimal volume ofcomplete RPMI 1640 in a tissue culture flask (ex. 30×10⁶ cells in 10 mLmedia/25 cm² flask). Cells are infected with HIV-1 or virus with variantintegrase generated as described below at a molecules of infection (moi)of 0.005. Cells are incubated for 1.5 h at 37° C. on a rotating rack ina 5% CO₂ incubator and re-suspended in complete RPMI to give a finalconcentration of 25,000-cells/175 μL. 175 μL of cell mix is added towells of a 96 well microtiter plate containing 25 μL 8× inhibitors.25,000 uninfected C8166-LTRIuc cells/well in 200 μL complete RPMI areadded to the last row for background control. Cells are incubated at 37°C. in 5% CO₂ incubator for 3 days.

Luciferase Assay

50 μL Steady Glo (luciferase substrate T_(1/2)=5 hours Promega catalogue#E2520) is added to each well of the 96 well plate. The relative lightunits (RLU) of luciferase is determined using the LUMIstar Galaxyluminometer (BMG LabTechnologies). Plates are read from the bottom for 2seconds per well with a gain of 240.

The level of inhibition (% inhibition) of each well containing inhibitoris calculated as follows:

${\% \cdot {inhibition}} = {\left( {1 - \left\lbrack \frac{{{RLU} \cdot {well}} - {{RLU} \cdot {blank}}}{{{RLU} \cdot {control}} - {{RLU} \cdot {blank}}} \right\rbrack} \right)*100}$

The calculated % inhibition values are used to determine EC₅₀, slopefactor (n) and maximum inhibition (I_(max)) by the non-linear regressionroutine NUN procedure of SAS using the following equation:

${\% \cdot {inhibition}} = \frac{I_{\max} \times \lbrack{inhibitor}\rbrack^{n}}{\lbrack{inhibitor}\rbrack^{n} + {IC}_{50}^{n}}$

TABLES OF COMPOUNDS

Compounds of the invention shown in Tables 1 to 4 are integraseinhibitors. Representative compounds selected from Tables 1 to 3 belowhave EC₅₀ values of no more than 20 μM when tested in the HIV-1luciferase assay of Example 46.

Retention times (t_(R)) for each compound are measured using thestandard analytical HPLC conditions described in the Examples. As iswell known to one skilled in the art, retention time values aresensitive to the specific measurement conditions. Therefore, even ifidentical conditions of solvent, flow rate, linear gradient, and thelike are used, the retention time values may vary when measured, forexample, on different HPLC instruments. Even when measured on the sameinstrument, the values may vary when measured, for example, usingdifferent individual HPLC columns, or, when measured on the sameinstrument and the same individual column, the values may vary, forexample, between individual measurements taken on different occasions.

TABLE 1

t_(R) MS Cpd R⁴ R⁵ R⁶ R⁷ R⁸ (min) (M + H)⁺ 1001

F H H H 4.7 402.1/ 404.1 1002

H —OCH₃ H H 4.6 414.1/ 416.1 1003

H H —OCH₃ H 4.7 414.2/ 416.1 1004

H H H F 5.1 402.1/ 404.1 1005

F H H H 5.7 420.1/ 422.1 1006

H —CH═CH₂ H H 5.4 410.1/ 412.1 1007

F H H H 4.9 442.2 1008

F H H H 5.1 442.1 1009

F H H H 4.9 442.1 1010

F H H H 5.2 442.1 1011

H —CN H H 5.4 409.2/ 411.2 1012

H —C(═O)H H H 4.9 412.2/ 414.2 1013

H —CH₂OH H H 4.2 414.2/ 416.2 1014

H —C≡CH H H 5.2 408.2/ 410.2 1015

F H H H 5.0 458.1/ 460.1 1016

F H H H 5.2 458.1/ 460.1 1017

F H H H 4.9 438.2 1018

H H H Br 8.8 462.1/ 464.1/ 466.1 1019

F H H H 3.9 459.2/ 461.2 1020

F H H H 4.2 459.2/ 461.2 1021

H H

H 4.5 499.3 1022

H H

H 5.4 531.2/ 533.2 1023

H H

H 5.4 531.2/ 533.2 1024

H H

H 5.4 517.3/ 519.3 1025

H H

H 5.6 517.3/ 519.3 1026

H H

H 3.7 532.3/ 534.2 1027

H H

H 5.5 547.3/ 549.3 1028

H H

H 5.7 547.3/ 549.3 1029

H H

H 5.4 547.3/ 549.3 1030

H H

H 3.7 518.3/ 520.3 1031

H H

H 3.8 518.3/ 520.3 1032

H H

H 3.7 518.3/ 520.3 1033

H H

H 3.8 518.3/ 520.3 1034

H H

H 3.4 532.3/ 534.3 1035

H H

H 3.6 532.3/ 534.3 1036

H Br H —CH₃ 5.4 498.2/ 500.2 1037

H

H H 5.3 517.2/ 519.2 1038

H

H H 5.5 517.2/ 519.2 1039

H H

H 4.2 497.3 1040

H

H H 4.5 519.3 1041

H H

H 4.1 517.2/ 519.2 1042

H H

H 4.2 517.2/ 519.2 1043

H H

H 4.1 517.2/ 519.2 1044

H H

H 4.2 517.2/ 519.2 1045

H H H —CH₂CH₃ 5.4 434.3 1046

H Br H —CH₂CH₃ 7.1 512.2/ 514.2 1047

H H

H 4.8 518.2/ 520.2 1048

H H

H 4.8 518.2/ 520.2 1049

H H

H 5.9 516.2/ 518.2 1050

H H

H 6.0 516.2/ 518.2 1051

H Br H —OCF₃ 8.2 568.1/ 570.1 1052

H H H —CH₃ 5.0 420.3 1053

H H

H 5.5 523.2/ 525.2 1054

H H

H 5.0 523.2/ 525.2 1055

H H

H 5.5 519.2/ 521.2 1056

H H H

5.3 517.2/ 519.2 1057

H H H

5.5 517.2/ 519.2 1058

H H H

5.3 547.2/ 549.2 1059

H H H

5.6 547.2/ 549.2 1060

H H H

5.3 547.2/ 549.2 1061

H H H

5.5 547.2/ 549.2 1062

H H H

4.3 518.2/ 520.2 1063

H H H

4.6 518.2/ 520.2 1064

H H H

5.9 531.2/ 533.2 1065

H H H

6.1 531.2/ 533.2 1066

H H H

4.3 518.2/ 520.2 1067

H H H

4.5 518.2/ 520.2 1068

H H

H 5.4 523.2/ 525.2 1069

H H

H 5.1 523.2/ 525.2 1070

H H

H 5.7 519.3/ 521.2 1071

H H

H 3.5 553.3/ 555.3 1072

H H H Br 5.6 519.1/ 521.1 1073

H H H Br 6.0 519.1/ 521.1 1074

H H

H 3.5 539.3/ 541.3 1075

H H H

4.8 610.1/ 612.1 1076

H H H

5.1 610.1/ 612.1 1077

H H H

4.5 560.2/ 562.2 1078

H H H

4.7 560.2/ 562.2 1079

H H H

4.8 588.2/ 590.2 1080

H H H

5.1 588.2/ 590.2 1081

H H H

4.8 630.2/ 632.2 1082

H H H

5.0 630.2/ 632.2 1083

H H H

5.3 608.2/ 610.2/ 612.2 1084

H H H

5.5 608.2/ 610.2/ 612.2 1085

H H H OCF₃ 6.3 490.2 1086

H H

6.0 456.2 1087

H H H

5.0 467.2/ 469.2 1088

H H H

4.8 469.2/ 471.2 1089

H H H

4.6 507.2/ 509.1 1090

F H H H 5.7 420.1/ 422.1 1091

F H H H 3.8 461.2 1092

H H Me Cl 5.0 491.2/ 493.2 1093

H F Me H 2.9 475.1 1094

H H CN H 4.3 468.0 1095

H H CN H 5.5 431.1 1096

H H —C(═O)— NH—t-Bu H 4.3 542.1

TABLE 2

t_(R) MS Cpd R² R⁴ (min) (M + H)⁺ 2001

5.1 469.3/ 471.3 2002

5.0 491.4 2003

5.0 472.4 2004

5.2 569.3 2005

6.6 498.3 2006

6.8 512.3 2007

6.8 512.3 2008

6.5 533.2/ 535.2 2009

6.7 533.2/ 535.2 2010

5.0 499.4 2011

6.0 500.3 2012

6.7 569.3 2013

5.5 500.3 2014

8.3 555.2 2015 —CH₂OCH₃

4.8 436.2 2016

8.2 643.0/ 645.0/ 647.0 2017

8.1 643.0/ 645.0/ 647.0

TABLE 3

t_(R) MS Cpd R⁴ R⁵ R⁶ R⁷ R⁸ (min) (M + H)⁺ 3001

F H H H 4.7 402.0 3002

H H H F 5.2 402.1 3003

—OCH₃ H H H 4.5 414.2/ 416.2 3004

H —OCH₃ H H 4.6 414.1/ 416.1 3005

H H —OCH₃ H 4.6 414.1/ 416.1 3006

H H H —OCH₃ 4.5 414.1/ 416.1 3007

H H H —CH₃ 4.7 398.1/ 400.1 3008

H H —CH═CH₂ H 4.9 410.2/ 412.2 3009

H H

H 5.2 424.2/ 426.2 3010

F H H H 5.0 424.2 3011

H H —NO₂ H 7.5 429.1/ 431.1 3012

H H —NH₂ H 5.2 399.1/ 401.1 3013

H H —CH₂OH H 4.9 414.1/ 416.1 3014

H H —C(═O)NH₂ H 4.7 427.1/ 429.1 3015

H H —CN H 6.5 409.1/ 411.1 3016

H H —NHC(═O)CH₃ H 5.0 441.1/ 443.1 3017

—CH₃ H H H 4.0 398.3 3018

—CH₃ H H H 4.0 420.4 3019

H H H

5.3 477.2/ 479.2

TABLE 4

Cpd R⁴ R⁵ R⁶ R⁷ R⁸ R² 4001

H H H

CH₃ 4002

H H

H CH₃ 4003

H H H H

4004

H H H

CH₃ 4005

H H

H CH₃ 4006

H H H

CH₃ 4007

H H H H

All of the documents cited herein are incorporated in to the inventionas a reference, as if each of them is individually incorporated.Further, it would be appreciated that, in the above teaching ofinvention, the skilled in the art could make certain changes ormodifications to the invention, and these equivalents would still bewithin the scope of the invention defined by the appended claims of theapplication.

1. A compound of the formula (I)

wherein R² is selected from: a) (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl, Het, halo, nitro or cyano; b)—C(═O)—R¹¹, —C(═O)—O—R¹¹, —S—R¹¹, —SO—R¹¹, —SO₂—R¹¹,—(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,—(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,—(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or—(C₁₋₆)alkylene-SO₂—R¹¹; wherein R¹¹ is in each instance independentlyselected from H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and wherein each of thearyl and Het is optionally substituted with 1 to 3 substituents eachindependently selected from: i) halo, oxo, thioxo, (C₂₋₆)alkenyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,—O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl, —SO(C₁₋₆)alkyl,—SO₂(C₁₋₆)alkyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄)alkyl,—C(═O)—N((C₁₋₄)alkyl)₂, —C(═O)-aryl, —C(═O)—Het, NH₂, —NH(C₁₋₆)alkyl and—N((C₁₋₆)alkyl)₂; ii) (C₁₋₆)alkyl optionally substituted with —OH,—O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and iii) aryl or Het, whereineach of the aryl and Het is optionally substituted with halo,(C₁₋₆)alkyl or COOH; and c) —O—R^(8a) wherein R^(8a) is selected from H,(C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryland Het; d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰,—SO₂—N(R⁹)R¹⁰, —(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,—(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰wherein R⁹ is in each instance independently selected from H,(C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and R¹⁰ is in each instanceindependently selected from R¹¹, —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹,—C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are asdefined above; or R² may also be H, (C₁₋₆)alkyl or —O—(C₁₋₆)alkyl whenone of R⁵ or R⁸ is other than H or when one of R⁶ or R⁷ is other than H,halo, (C₁₋₆)alkyl or (C₁₋₆)haloalkyl, R⁵ and R⁸ are each independentlyselected from: a) halo, nitro or cyano; b) R¹¹, —C(═O)—R¹¹,—C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —SO—R¹¹, —SO₂—R¹¹, —(C₁₋₆)alkylene-R¹¹,—(C₁₋₆)alkylene-C(═O)—R¹¹, —(C₁₋₆)alkylene-C(═O)—O—R¹¹,—(C₁₋₆)alkylene-O—R¹¹, —(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or—(C₁₋₆)alkylene-SO₂—R¹¹; wherein R¹¹ is in each instance independentlyselected from H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and wherein each of thearyl and Het is optionally substituted with 1 to 3 substituents eachindependently selected from: i) halo, oxo, thioxo, (C₂₋₆)alkenyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH,—O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl, —SH, —S(C₁₋₆)alkyl, —SO(C₁₋₆)alkyl,—SO₂(C₁₋₆)alkyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄)alkyl,—C(═O)—N((C₁₋₄)alkyl)₂, —C(═O)-aryl, —C(═O)—Het, NH₂, —NH(C₁₋₆)alkyl and—N((C₁₋₆)alkyl)₂; ii) (C₁₋₆)alkyl optionally substituted with —OH,—O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and iii) aryl or Het, whereineach of the aryl and Het is optionally substituted with halo,(C₁₋₆)alkyl or COOH; and c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰,—O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰, —(C₁₋₆)alkylene-N(R⁹)R¹⁰,—(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰, —(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or—(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰ wherein R⁹ is in each instanceindependently selected from H, (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and R¹⁰is in each instance independently selected from R¹¹,—(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and—C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are as defined above; R⁶ is selectedfrom: a) (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl, nitro, cyano,aryl and Het; b) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —SO—R¹¹,—SO₂—R¹¹, —(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,—(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,—(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or—(C₁₋₆)alkylene-SO₂—R¹¹; wherein R¹¹ is in each instance independentlyselected from H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and c) —N(R⁹)R¹⁰,—C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,—(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰wherein R⁹ is in each instance independently selected from H,(C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and R¹⁰ is in each instanceindependently selected from R¹¹, —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹,—C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are asdefined above; wherein each of the aryl and Het is optionallysubstituted with 1 to 3 substituents each independently selected from:i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH, —O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl,—SH, —S(C₁₋₆)alkyl, —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —NH₂,—NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂; ii) (C₁₋₆)alkyl optionallysubstituted with —OH, —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and iii)aryl or Het, wherein each of the aryl and Het is optionally substitutedwith halo, (C₁₋₆)alkyl or COOH; and R⁶ may also be H, halo, (C₁₋₆)alkyl,or (C₁₋₆)haloalkyl when at least one of R⁵ or R⁸ is other than H or whenR⁷ is other than H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when R² isother than H, (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl; R⁷ is selected from: a)(C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl, nitro, cyano, aryl andHet; b) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —SO—R¹¹, —SO₂—R¹¹,—(C₁₋₆)alkylene-R¹¹, —(C₁₋₆)alkylene-C(═O)—R¹¹,—(C₁₋₆)alkylene-C(═O)—O—R¹¹, —(C₁₋₆)alkylene-O—R¹¹,—(C₁₋₆)alkylene-S—R¹¹, —(C₁₋₆)alkylene-SO—R¹¹ or—(C₁₋₆)alkylene-SO₂—R¹¹; wherein R¹¹ is in each instance independentlyselected from H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and c) —N(R⁹)R¹⁰,—C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁₋₆)alkylene-N(R⁹)R¹⁰, —(C₁₋₆)alkylene-C(═O)—N(R⁹)R¹⁰,—(C₁₋₆)alkylene-O—C(═O)—N(R⁹)R¹⁰, or —(C₁₋₆)alkylene-SO₂—N(R⁹)R¹⁰wherein R⁹ is in each instance independently selected from H,(C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and R¹⁰ is in each instanceindependently selected from R¹¹, —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹,—C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are asdefined above; wherein each of the aryl and Het is optionallysubstituted with 1 to 3 substituents each independently selected from:i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH, —O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl,—SH, —S(C₁₋₆)alkyl, —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —NH₂,—NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂; ii) (C₁₋₆)alkyl optionallysubstituted with —OH, —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and iii)aryl or Het, wherein each of the aryl and Het is optionally substitutedwith halo, (C₁₋₆)alkyl or COOH; and R⁷ may also be H, halo, (C₁₋₆)alkyl,or (C₁₋₆)haloalkyl when at least one of R⁵ or R⁸ is other than H or whenR⁶ is other than H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when R² isother than H, (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl; or R⁵ and R⁶, togetherwith the C to which they are attached, R⁶ and R⁷, together with the C towhich they are attached, or R⁷ and R⁸, together with the C to which theyare attached; may be linked to form a 5- or 6-membered carbocycle or a4- to 7-membered heterocycle optionally further containing 1 to 3heteroatoms each independently selected from N, O and S, wherein each Sheteroatom may, independently and where possible, exist in an oxidizedstate such that it is further bonded to one or two oxygen atoms to formthe groups SO or SO₂; wherein the carbocycle or heterocycle isoptionally substituted with 1 to 3 substituents each independentlyselected from halo, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,(C₃₋₇)cycloalkyl, —OH, —O(C₁₋₆)alkyl, —SH, —S(C₁₋₆)alkyl, —NH₂,—NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂; R³ is (C₁₋₆)alkyl, (C₁₋₆)haloalkyl,(C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-,aryl-(C₁₋₆)alkyl-, Het-(C₁₋₆)alkyl- or —Y—R³¹, and bond c is a singlebond; or R³ is (C₁₋₆)alkylidene and bond c is a double bond; wherein Yis O or S and R³¹ is (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, (C₂₋₆)alkenyl,(C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl, aryl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-,aryl-(C₁₋₆)alkyl- or Het-(C₁₋₆)alkyl-; wherein each of the(C₁₋₆)alkylidene, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, (C₂₋₆)alkenyl,(C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, aryl-(C₁₋₆)alkyl-,Het-(C₁₋₆)alkyl- and —Y—R³¹ is optionally substituted with 1 to 3substituents each independently selected from (C₁₋₆) alkyl, halo, cyano,oxo and —O(C₁₋₆)alkyl; R⁴ is aryl or Het, wherein each of the aryl andHet is optionally substituted with 1 to 5 substituents eachindependently selected from halo, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, —OH, —O(C₁₋₆)alkyl, —SH,—S(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆) alkyl and —N((C₁₋₆)alkyl)₂; wherein the(C₁₋₆)alkyl is optionally substituted with hydroxy, —O(C₁₋₆)alkyl, cyanoor oxo; wherein Het is a 4- to 7-membered saturated, unsaturated oraromatic heterocycle having 1 to 4 heteroatoms each independentlyselected from O, N and S, or a 7- to 14-membered saturated, unsaturatedor aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms,each independently selected from O, N and S; wherein each N heteroatommay, independently and where possible, exist in an oxidized state suchthat it is further bonded to an oxygen atom to form an N-oxide group andwherein each S heteroatom may, independently and where possible, existin an oxidized state such that it is further bonded to one or two oxygenatoms to form the groups SO or SO₂; or a pharmaceutically acceptablesalt thereof.
 2. A compound according to claim 1 of the formula (Ib),

wherein R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 2, or a pharmaceutically acceptable salt thereof, wherein R² isselected from H, (C₁₋₆)alkyl or —O—(C₁₋₆)alkyl when one of R⁵ or R⁸ isother than H or when one of R⁶ or R⁷ is other than H, halo, (C₁₋₆)alkylor (C₁₋₆)haloalkyl.
 4. A compound according to claim 2, or apharmaceutically acceptable salt thereof, wherein R³ is selected from—O(C₁₋₆)alkyl, —O—(C₁₋₆)haloalkyl, —O(C₂₋₆)alkenyl, —O(C₂₋₆)alkynyl or—O—(C₃₋₇)cycloalkyl; wherein each of the —O(C₁₋₆)alkyl and—O—(C₃₋₇)cycloalkyl is optionally substituted with 1 to 3 substituentseach independently selected from (C₁₋₃)alkyl, cyano, oxo and —O(C₁₋₆)alkyl; and bond c is a single bond.
 5. A compound according to claim 2,or a pharmaceutically acceptable salt thereof, wherein R⁴ is selectedfrom phenyl optionally substituted with 1 to 3 substituents eachindependently selected from halo, (C₁₋₄)alkyl and (C₁₋₄)haloalkyl.
 6. Acompound according to claim 2, or a pharmaceutically acceptable saltthereof, wherein R⁴ is Het optionally substituted with 1 to 3substituents each independently selected from halo and (C₁₋₆)alkyl;wherein the Het is a 5- or 6-membered heterocycle having 1 to 3heteroatoms each independently selected from N, O and S; or the Het is a9- or 10-membered heteropolycycle having 1 to 3 heteroatoms eachindependently selected from N, O and S.
 7. A compound according to claim2, or a pharmaceutically acceptable salt thereof, wherein R⁵ is H, halo,(C₁₋₆)alkyl, (C₁₋₆)haloalkyl or —O(C₁₋₆) alkyl.
 8. A compound accordingto any claim 2, or a pharmaceutically acceptable salt thereof, whereinR⁶ is H when at least one of R⁵ or R⁸ is other than H or when R⁷ isother than H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when R² is otherthan H, (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl.
 9. A compound according to claim2, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selectedfrom: a) (C₂₋₆)alkenyl, (C₃₋₇)cycloalkyl, nitro, cyano, aryl and Het; b)—(C₁₋₆)alkylene-R¹¹, wherein R¹¹ is in each instance independentlyselected from H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; and c) —N(R⁹)R¹⁰,—C(═O)—N(R⁹)R¹⁰, wherein R⁹ is in each instance independently selectedfrom H, (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and R¹⁰ is in each instanceindependently selected from R¹¹, —(C₁₋₆)alkylene-R¹¹, —SO₂—R¹¹,—C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹¹; wherein R¹¹ and R⁹ are asdefined above; wherein each of the aryl and Het is optionallysubstituted with 1 to 3 substituents each independently selected from:i) halo, oxo, thioxo, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-, —OH, —O(C₁₋₆)alkyl, —O(C₁₋₆)haloalkyl,—SH, —S(C₁₋₆)alkyl, —SO(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —NH₂,—NH(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂; ii) (C₁₋₆)alkyl optionallysubstituted with —OH, —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and iii)aryl or Het, wherein each of the aryl and Het is optionally substitutedwith halo, (C₁₋₆)alkyl or COOH; R⁷ may also be H, halo, (C₁₋₆)alkyl, or(C₁₋₆)haloalkyl when at least one of R⁵ or R⁸ is other than H or when R⁶is other than H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when R² isother than H, (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl.
 10. A compound accordingto claim 2, or a pharmaceutically acceptable salt thereof, wherein R⁷ isH, when at least one of R⁵ or R⁸ is other than H or when R⁶ is otherthan H, halo, (C₁₋₆)alkyl, or (C₁₋₆)haloalkyl or when R² is other thanH, (C₁₋₆)alkyl, or —O—(C₁₋₆)alkyl.
 11. A compound according to claim 2,or a pharmaceutically acceptable salt thereof, wherein R⁸ is selectedfrom: a) F, Cl, Br; and b) H, (C₁₋₃)alkyl, —O—(C₁₋₃)haloalkyl, phenyland Het, —(C₁₋₃)alkylene-phenyl, —(C₁₋₃)alkylene-Het; wherein each ofthe aryl and Het is optionally substituted with 1 to 2 substituents eachindependently selected from: i) oxo, thioxo, —O(C₁₋₆)alkyl, —C(═O)—NH₂,—C(═O)—NH(C₁₋₄)alkyl, —C(═O)—N((C₁₋₄)alkyl)₂, —C(═O)-aryl, —C(═O)-Het;and ii) (C₁₋₆)alkyl.
 12. A pharmaceutical composition comprising atherapeutically a compound according to claim 2, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 13.A method for treating HIV in a host infected by HIV which methodcomprises administering to such host a therapeutically effective amountof a compound according to claim 2, or a pharmaceutically acceptablesalt thereof.